Fault discrimination and responsive processing based on data and context

ABSTRACT

Systems and methods disclosed here provide ways to discriminate fault types encountered in analyte sensors and systems and further provide ways to process such discriminated faults responsively based on sensor data, clinical context information, and other data about the patient or patient&#39;s environment. The systems and methods thus employ clinical context in detecting and/or responding to errors or faults associated with an analyte sensor system, and discriminating the type of fault, and its root cause, particularly as fault dynamics can appear similar to the dynamics of physiological systems, emphasizing the importance of discriminating the fault and providing appropriate responsive processing. Thus, the disclosed systems and methods consider the context of the patient&#39;s health condition or state in determining how to respond to the fault.

CROSS-REFERENCE TO RELATED APPLICATION

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application claims the benefit of U.S. ProvisionalApplication No. 62/009,065, filed Jun. 6, 2014. The aforementionedapplication is incorporated by reference herein in its entirety, and ishereby expressly made a part of this specification.

TECHNICAL FIELD

The present embodiments relate to continuous analyte monitoring, and, inparticular, to fault discrimination and responsive processing within acontinuous analyte monitoring system.

BACKGROUND

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin-dependent) and/or in which insulinis not effective (Type II or non-insulin-dependent). In the diabeticstate, the patient or user suffers from high blood sugar, which cancause an array of physiological derangements associated with thedeterioration of small blood vessels, for example, kidney failure, skinulcers, or bleeding into the vitreous of the eye. A hypoglycemicreaction (low blood sugar) can be induced by an inadvertent overdose ofinsulin, or after a normal dose of insulin or glucose—lowering agentaccompanied by extraordinary exercise or insufficient food intake.

Conventionally, a person with diabetes carries a self—monitoring bloodglucose (SMBG) monitor, which typically requires uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a personwith diabetes normally only measures his or her glucose levels two tofour times per day. Unfortunately, such time intervals are so far spreadapart that the person with diabetes likely finds out too late of ahyperglycemic or hypoglycemic condition, sometimes incurring dangerousside effects. It is not only unlikely that a person with diabetes willbecome aware of a dangerous condition in time to counteract it, but itis also likely that he or she will not know whether his or her bloodglucose value is going up (higher) or down (lower) based on conventionalmethod. Diabetics thus may be inhibited from making educated insulintherapy decisions.

Another device that some diabetics used to monitor their blood glucoseis a continuous analyte sensor, e.g., a continuous glucose monitor(CGM). A CGM typically includes a sensor that is placed invasively,minimally invasively or non-invasively. The sensor measures theconcentration of a given analyte within the body, e.g., glucose, andgenerates a raw signal that is generated by electronics associated withthe sensor. The raw signal is converted into an output value that isrendered on a display. The output value that results from the conversionof the raw signal is typically expressed in a form that provides theuser with meaningful information, and in which form users becomefamiliar with analyzing, such as blood glucose expressed in mg/dL.

The above discussion assumes a reliable and true raw signal is receivedby the electronics. In some cases, faults or errors are encountered andthe signal is no longer reliable and true. Prior art approaches todetecting such are generally of a “one-size-fits-all” approach, as issystems' response to the same.

Faults or errors may be caused in a number of ways. For example, theymay be associated with a physiological activity in the host, e.g.,metabolic responses, or may also be associated with an in vivo portionof the sensor as the same settles into the host environment. They mayalso be associated with transient events within the control of apatient, or associated with the external environment surrounding thedevice. Other such are also seen.

Additionally, in the case of glucose monitoring, as glucose levels andpatterns vary from patient-to-patient and even within a patient fromday-to-day, noise may be difficult to differentiate from large glucoseswings. Similarly, a solution that is best for a patient with stableglucose at one particular time may not be the best solution for the sameor different patient at or near hypoglycemia or hyperglycemia, forexample.

SUMMARY

The present embodiments have several features, no single one of which issolely responsible for their desirable attributes. Without limiting thescope of the present embodiments as expressed by the claims that follow,their more prominent features now will be discussed briefly. Afterconsidering this discussion, and particularly after reading the sectionentitled “Detailed Description,” one will understand how the features ofthe present embodiments provide the advantages described herein.

Systems and methods according to present principles appreciate thatclinical context matters in detecting and/or responding to errors orfaults associated with an analyte sensor system. The same furtherunderstand that the clinical context bears on discriminating the type offault, and its root cause, particularly as fault dynamics can appearsimilar to glycemic dynamics, emphasizing the importance ofdiscriminating the fault and providing appropriate responsiveprocessing. Thus, the disclosed systems and methods further consider thecontext of the patient's health condition or state in determining how torespond to the fault. In this way, clinical context adds an element ofknowledge of clinical risk (e.g., acuity of disease state) in theinterpretation of the sensor data, and thus in the processing anddisplay of sensor data.

In a first aspect, a method is provided for discriminating a fault typein a continuous in vivo analyte monitoring system, including: receivinga signal from an analyte monitor; receiving clinical context data;evaluating the clinical context data against clinical context criteriato determine clinical context information; discriminating the fault typebased on both the received signal from the analyte monitor and theclinical context information; and performing responsive processing basedon at least the discriminated fault type.

In a second aspect, a method is provided for discriminating a fault typein a continuous in vivo analyte monitoring system, including: receivinga signal from an analyte monitor; receiving clinical context data;evaluating the clinical context data against clinical context criteriato determine clinical context information; discriminating the fault typebased on only the received signal; performing responsive processingbased on the discriminated fault type and the determined clinicalcontext information.

In a third aspect, a method is provided for performing responsiveprocessing in response to a fault in a continuous in vivo analytemonitoring system, including: receiving a signal from an analytemonitor; receiving clinical context data; evaluating the receivedclinical context data against clinical context criteria to determineclinical context information; performing responsive processing based onat least the received signal and the determined clinical contextinformation.

In a fourth aspect, a method is provided for discriminating a fault typein a continuous in vivo analyte monitoring system, including: receivinga signal from an analyte monitor; receiving clinical context data;transforming the clinical context data into clinical contextinformation; discriminating the fault type based on both the receivedsignal from the analyte monitor and the clinical context information;and performing responsive processing based on at least the discriminatedfault type.

In a fifth aspect, a method is provided for discriminating a fault typein a continuous in vivo analyte monitoring system, including: receivinga signal from an analyte monitor; evaluating the received signal againstfault discrimination criteria to determine fault information;determining clinical context information; discriminating the fault typebased on both the fault information and the clinical contextinformation; and performing responsive processing based on at least thediscriminated fault type.

Implementations of the above-noted aspects may include one or more ofthe following. The discriminating may include categorizing the faultbased on the received signal, the clinical context information, or both.The discriminating may include categorizing the fault based on thereceived signal, the clinical context information, or both, and wherethe categorizing the fault includes categorizing the fault as a sensorenvironment fault or as a system error/artifact fault. Thediscriminating may include categorizing the fault as a sensorenvironment fault, and further including subcategorizing the fault as acompression fault or an early wound response fault. The discriminatingmay include determining if the received signal or the received datamatches or meets a predetermined criterion. The discriminating mayinclude analyzing the signal using a time-based technique, afrequency-based technique, or a wavelet-based technique. Thediscriminating may include raw signal analysis, residualized signalanalysis, pattern analysis, and/or slow versus fast sampling. Thediscriminating may include projecting the received signal onto aplurality of templates, each template corresponding to a fault mode. Thediscriminating may include variability analysis or fuzzy logic analysis.The received clinical context data may be selected from the groupconsisting of: age, anthropometric data, drugs currently operating onthe patient, temperature as compared to a criteria, a fault history ofthe patient, activity level of the patient, exercise level of thepatient, a patient level of interaction with a glucose monitor, patternsof glucose signal values, clinical glucose value and its derivatives, arange of patient glucose levels over a time period, a duration overwhich patient glucose levels are maintained in a range, a patientglucose state, a glycemic urgency index, time of day, or pressure. Themethod may further include processing the signal, e.g., where theprocessing removes or filters noise from the signal. The method mayfurther include receiving an additional signal, such as a sensortemperature signal, an impedance signal, an oxygen signal, a pressuresignal, or a background signal. The clinical context information maycorrespond to data about the patient excluding a signal value measuredat a sensor associated with the analyte monitor.

The clinical context criteria may include predefined values or ranges ofparameters selected from the group consisting of: drugs currentlyoperating on the patient, temperature, a fault history of the patient,activity level of the patient, exercise level of the patient, a patientlevel of interaction with a glucose monitor, patterns of glucose signalvalues, clinical glucose value and its derivatives, a range of patientglucose levels over a time period, a duration over which patient glucoselevels are maintained in a range, a patient glucose state, a glycemicurgency index, time of day, or pressure. The clinical context data mayinclude temperature, the clinical context criteria may include a patternof temperatures, the evaluating may determine the clinical contextinformation to be that the user is in contact with water at the sensorsite, and the discriminating the fault type may include discriminatingthe fault type as water ingress. The clinical context data may includepatient activity level or time of day, the clinical context criteria mayinclude a pattern of patient activity levels, the evaluating maydetermine the clinical context information to be that the user iscompressing the sensor site, and the discriminating the fault type mayinclude discriminating the fault type as compression. The clinicalcontext data may include time since implant, the clinical contextcriteria may include a range of times since implant in which dip andrecover faults are likely, the evaluating may determine the clinicalcontext information to be that the sensor is recently implanted, and thediscriminating the fault type may include discriminating the fault typeas a dip and recover fault. The clinical context data may include aclinical glucose value and a datum selected from the group consistingof: age, anthropometric data, activity, exercise, clinical use of data,or patient interaction with monitor.

The responsive processing may include providing a display to a user, thedisplay including a warning, an alert, an alarm, a confidence indicator,a range of values, a predicted value, or a blank screen. The performingresponsive processing may include adjusting a level of filtering of thereceived signal. The performing responsive processing may includeperforming a prediction of a future signal value based on the receivedsignal. The performing responsive processing may include performing aself diagnostics routine. The performing responsive processing mayinclude performing a step of compensation. The performing responsiveprocessing may include switching from a first therapeutic mode to asecond therapeutic mode.

In a sixth aspect, a system is provided for performing any of the abovemethods.

In a seventh aspect, a device is provided substantially as shown and/ordescribed the specifications and/or drawings.

In an eighth aspect, a method is provided substantially as shown and/ordescribed the specifications and/or drawings.

In a ninth aspect, an electronic device is provided for monitoring dataassociated with a physiological condition, including: a continuousanalyte sensor, where the continuous analyte sensor is configured tosubstantially continuously measure the concentration of analyte in thehost, and to provide continuous sensor data associated with the analyteconcentration in the host; and a processor module configured to performa method substantially as shown and/or described the specificationsand/or drawings. The analyte may be glucose.

In a tenth aspect, electronic device is provided for delivering amedicament to a host, the device including: a medicament delivery deviceconfigured to deliver medicament to the host, where the medicamentdelivery device is operably connected to a continuous analyte sensor,where the continuous analyte sensor is configured to substantiallycontinuously measure the concentration of analyte in the host, and toprovide continuous sensor data associated with the analyte concentrationin the host; and a processor module configured to perform a methodsubstantially as shown and/or described the specifications and/ordrawings. The analyte may be glucose and the medicament may be insulin.

To ease the understanding of the described features, continuous glucosemonitoring is used as part of the explanations that follow. It will beappreciated that the systems and methods described are applicable toother continuous monitoring systems, e.g., of analytes. For example, thefeatures discussed may be used for continuous monitoring of lactate,free fatty acids, heart rate during exercise, IgG-anti gliadin, insulin,glucagon, movement tracking, fertility, caloric intake, hydration,salinity, sweat/perspiration (stress), ketones, adipanectin, troponin,perspiration, and/or body temperature. Where glucose monitoring is usedas an example, one or more of these alternate examples of monitoringconditions may be substituted.

Any of the features of embodiments of the various aspects disclosed isapplicable to all aspects and embodiments identified. Moreover, any ofthe features of an embodiment is independently combinable, partly orwholly with other embodiments described herein, in any way, e.g., one,two, or three or more embodiments may be combinable in whole or in part.Further, any of the features of an embodiment of the various aspects maybe made optional to other aspects or embodiments. Any aspect orembodiment of a method can be performed by a system or apparatus ofanother aspect or embodiment, and any aspect or embodiment of the systemcan be configured to perform a method of another aspect or embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

The present embodiments now will be discussed in detail with an emphasison highlighting the advantageous features. These embodiments depict thenovel and nonobvious fault discrimination and responsive processingsystems and methods shown in the accompanying drawings, which are forillustrative purposes only. These drawings include the followingfigures, in which like numerals indicate like parts:

FIG. 1A is an exploded perspective view of a glucose sensor in oneembodiment;

FIG. 1B is a perspective view schematic illustrating layers that form anin vivo portion of an analyte sensor, in one embodiment;

FIG. 1C is a side-view schematic illustrating a formed in vivo portionof an analyte sensor.

FIG. 2 is a block diagram that illustrates sensor electronics in oneembodiment;

FIGS. 3A-3D are schematic views of a receiver in first, second, third,and fourth embodiments, respectively;

FIG. 4 is a block diagram of receiver electronics in one embodiment;

FIG. 5 is a flowchart of a method according to present principles;

FIG. 6A is a more detailed flowchart of a method according to presentprinciples, showing in particular types of signals and methods ofperforming responsive signal processing; FIGS. 6B-6D are plotsindicating types of noise filtering.

FIG. 7 is a plot indicating the effect of temperature on noise;

FIGS. 8A-8D are plots indicating various types of faults, e.g.,compression (A), reference electrode depletion (B), the presence ofnoise (C), and a sensor fault discriminated by un-physiological behavior(D);

FIGS. 9A and 9B illustrate slow versus fast sampling;

FIGS. 10A-10D illustrate a flowchart and plots for applying fuzzy logicin noise determination;

FIG. 11 illustrates various types of clinical context information;

FIGS. 12A-12C illustrates aspects of a first regime of faultdiscrimination and responsive processing;

FIGS. 13A-13C illustrates aspects of a second regime of faultdiscrimination and responsive processing;

FIGS. 14A-14B illustrates aspects of a third regime of faultdiscrimination and responsive processing;

FIG. 15 is a flowchart of another exemplary method according to presentprinciples;

FIG. 16 illustrates one categorization scheme for fault discrimination;

FIG. 17 illustrates another categorization scheme for faultdiscrimination;

FIG. 18 illustrates a further categorization scheme for faultdiscrimination;

FIG. 19 is a flowchart of another exemplary method according to presentprinciples;

FIG. 20 is a look-up table for use in responsive processing;

FIG. 21 is another table for use in responsive processing;

FIG. 22 illustrates types of responsive signal processing;

FIGS. 23A-23B illustrate selective filtering based on a signal andclinical context; FIG. 23C illustrates a fuzzy membership function forthe use of fuzzy logic;

FIG. 24 illustrates a signal exhibiting a compression fault;

FIG. 25 illustrates a signal exhibiting a “dip-and-recover” fault;

FIG. 26 is a flowchart of another exemplary method according to presentprinciples;

FIG. 27 illustrates a signal exhibiting a “shower spike”;

FIG. 28 illustrates another signal exhibiting a compression fault;

FIGS. 29A-29B illustrate signals exhibiting a water ingress fault;

FIG. 30 illustrates a signal exhibiting end-of-life noise;

FIG. 31 illustrates another signal exhibiting a dip-and-recover fault;

FIG. 32 illustrates signals in which a lag error is present;

FIGS. 33A-33D illustrate another signal exhibiting a compression fault;

FIGS. 34A-34C illustrate a flowchart and signals for use in faultdiscrimination by way of template generation and matching;

FIGS. 35A-35C illustrate a number of examples of evaluations of signalsvis-à-vis templates;

FIG. 36 illustrates a transmitter with an integrated force sensor; and

FIG. 37 illustrates the use of linear regression in prediction orforecasting.

DETAILED DESCRIPTION Definitions

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “analyte” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a substance or chemicalconstituent in a biological fluid (for example, blood, interstitialfluid, cerebral spinal fluid, lymph fluid or urine) that can beanalyzed. Analytes can include naturally occurring substances,artificial substances, metabolites, and/or reaction products. In someembodiments, the analyte for measurement by the sensor heads, devices,and methods is analyte. However, other analytes are contemplated aswell, including but not limited to acarboxyprothrombin; acylcarnitine;adenine phosphoribosyl transferase; adenosine deaminase; albumin;alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-βhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, analyte-6-phosphate dehydrogenase, hemoglobin A,hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F,D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax,sexual differentiation, 21-deoxycortisol); desbutylhalofantrine;dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocytearginase; erythrocyte protoporphyrin; esterase D; fattyacids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; analyte-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and5-Hydroxyindoleacetic acid (FHIAA).

The term “ROM” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to read-only memory, which is atype of data storage device manufactured with fixed contents. ROM isbroad enough to include EEPROM, for example, which is electricallyerasable programmable read-only memory (ROM).

The term “RAM” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a data storage device for whichthe order of access to different locations does not affect the speed ofaccess. RAM is broad enough to include SRAM, for example, which isstatic random access memory that retains data bits in its memory as longas power is being supplied.

The term “A/D Converter” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to hardware and/orsoftware that converts analog electrical signals into correspondingdigital signals.

The terms “microprocessor” and “processor” as used herein are broadterms and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto a computer system, state machine, and the like that performsarithmetic and logic operations using logic circuitry that responds toand processes the basic instructions that drive a computer.

The term “RF transceiver” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to a radio frequencytransmitter and/or receiver for transmitting and/or receiving signals.

The term “jitter” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to noise above and below the meancaused by ubiquitous noise caused by a circuit and/or environmentaleffects; jitter can be seen in amplitude, phase timing, or the width ofthe signal pulse.

The terms “raw data stream” and “data stream” as used herein are broadterms and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto an analog or digital signal directly related to the measured glucosefrom the glucose sensor. In one example, the raw data stream is digitaldata in “counts” converted by an A/D converter from an analog signal(e.g., voltage or amps) and includes one or more data pointsrepresentative of a glucose concentration. The terms broadly encompass aplurality of time spaced data points from a substantially continuousglucose sensor, which comprises individual measurements taken at timeintervals ranging from fractions of a second up to, e.g., 1, 2, or 5minutes or longer. In another example, the raw data stream includes anintegrated digital value, wherein the data includes one or more datapoints representative of the glucose sensor signal averaged over a timeperiod.

The term “calibration” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the process of determining therelationship between the sensor data and the corresponding referencedata, which can be used to convert sensor data into meaningful valuessubstantially equivalent to the reference data, with or withoututilizing reference data in real time. In some embodiments, namely, incontinuous analyte sensors, calibration can be updated or recalibrated(at the factory, in real time and/or retrospectively) over time aschanges in the relationship between the sensor data and reference dataoccur, for example, due to changes in sensitivity, baseline, transport,metabolism, and the like.

The terms “calibrated data” and “calibrated data stream” as used hereinare broad terms and are to be given their ordinary and customary meaningto a person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto data that has been transformed from its raw state to another stateusing a function, for example a conversion function, to provide ameaningful value to a user.

The terms “smoothed data” and “filtered data” as used herein are broadterms and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto data that has been modified to make it smoother and more continuousand/or to remove or diminish outlying points, for example, by performinga moving average of the raw data stream. Examples of data filtersinclude FIR (finite impulse response), IIR (infinite impulse response),moving average filters, and the like.

The terms “smoothing” and “filtering” as used herein are broad terms andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and furthermore refer without limitation tomodification of a set of data to make it smoother and more continuous orto remove or diminish outlying points, for example, by performing amoving average of the raw data stream.

The term “algorithm” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a computational process (forexample, programs) involved in transforming information from one stateto another, for example, by using computer processing.

The term “matched data pairs” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to reference data(for example, one or more reference analyte data points) matched withsubstantially time corresponding sensor data (for example, one or moresensor data points).

The term “counts” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a unit of measurement of adigital signal. In one example, a raw data stream measured in counts isdirectly related to a voltage (e.g., converted by an A/D converter),which is directly related to current from the working electrode. Inanother example, counter electrode voltage measured in counts isdirectly related to a voltage.

The term “sensor” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the component or region of adevice by which an analyte can be quantified.

The term “needle” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a slender instrument forintroducing material into or removing material from the body.

The terms “glucose sensor” and “member for determining the amount ofglucose in a biological sample” as used herein are broad terms and areto be given their ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and furthermore refer without limitation to any mechanism(e.g., enzymatic or non-enzymatic) by which glucose can be quantified.For example, some embodiments utilize a membrane that contains glucoseoxidase that catalyzes the conversion of oxygen and glucose to hydrogenperoxide and gluconate, as illustrated by the following chemicalreaction:

Glucose+O₂→Gluconate+H₂O₂

Because for each glucose molecule metabolized, there is a proportionalchange in the co-reactant O₂ and the product H₂O₂, one can use anelectrode to monitor the current change in either the co-reactant or theproduct to determine glucose concentration.

The terms “operably connected” and “operably linked” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto one or more components being linked to another component(s) in amanner that allows transmission of signals between the components. Forexample, one or more electrodes can be used to detect the amount ofglucose in a sample and convert that information into a signal, e.g., anelectrical or electromagnetic signal; the signal can then be transmittedto an electronic circuit. In this case, the electrode is “operablylinked” to the electronic circuitry. These terms are broad enough toinclude wireless connectivity.

The term “determining” encompasses a wide variety of actions. Forexample, “determining” may include calculating, computing, processing,deriving, investigating, looking up (e.g., looking up in a table, adatabase or another data structure), ascertaining and the like. Also,“determining” may include receiving (e.g., receiving information),accessing (e.g., accessing data in a memory) and the like. Also,“determining” may include resolving, selecting, choosing, calculating,deriving, establishing and/or the like.

The term “message” encompasses a wide variety of formats fortransmitting information. A message may include a machine readableaggregation of information such as an XML document, fixed field message,comma separated message, or the like. A message may, in someimplementations, include a signal utilized to transmit one or morerepresentations of the information. While recited in the singular, itwill be understood that a message may becomposed/transmitted/stored/received/etc. in multiple parts.

The term “substantially” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to being largely butnot necessarily wholly that which is specified.

The term “proximal” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to near to a point of referencesuch as an origin, a point of attachment, or the midline of the body.For example, in some embodiments of a glucose sensor, wherein theglucose sensor is the point of reference, an oxygen sensor locatedproximal to the glucose sensor will be in contact with or nearby theglucose sensor such that their respective local environments are shared(e.g., levels of glucose, oxygen, pH, temperature, etc. are similar).

The term “distal” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to spaced relatively far from apoint of reference, such as an origin or a point of attachment, ormidline of the body. For example, in some embodiments of a glucosesensor, wherein the glucose sensor is the point of reference, an oxygensensor located distal to the glucose sensor will be sufficiently farfrom the glucose sensor such their respective local environments are notshared (e.g., levels of glucose, oxygen, pH, temperature, etc. may notbe similar).

The term “domain” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a region of the membrane systemthat can be a layer, a uniform or non-uniform gradient (for example, ananisotropic region of a membrane), or a portion of a membrane.

The terms “in vivo portion” and “distal portion” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto the portion of the device (for example, a sensor) adapted forinsertion into and/or existence within a living body of a host.

The terms “ex vivo portion” and “proximal portion” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto the portion of the device (for example, a sensor) adapted to remainand/or exist outside of a living body of a host.

The term “electrochemical cell” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to a device in whichchemical energy is converted to electrical energy. Such a cell typicallyconsists of two or more electrodes held apart from each other and incontact with an electrolyte solution. Connection of the electrodes to asource of direct electric current renders one of them negatively chargedand the other positively charged. Positive ions in the electrolytemigrate to the negative electrode (cathode) and there combine with oneor more electrons, losing part or all of their charge and becoming newions having lower charge or neutral atoms or molecules; at the sametime, negative ions migrate to the positive electrode (anode) andtransfer one or more electrons to it, also becoming new ions or neutralparticles. The overall effect of the two processes is the transfer ofelectrons from the negative ions to the positive ions, a chemicalreaction.

The term “electrical potential” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to the electricalpotential difference between two points in a circuit which is the causeof the flow of a current.

The term “host” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to mammals, particularly humans.

The term “continuous analyte (or glucose) sensor” as used herein is abroad term and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and furthermore refers withoutlimitation to a device that continuously or continually measures aconcentration of an analyte, for example, at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes, or longer.In one exemplary embodiment, the continuous analyte sensor is a glucosesensor such as described in U.S. Pat. No. 6,001,067, which isincorporated herein by reference in its entirety.

The term “continuous analyte (or glucose) sensing” as used herein is abroad term and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and furthermore refers withoutlimitation to the period in which monitoring of an analyte iscontinuously or continually performed, for example, at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes, or longer.

The terms “reference analyte monitor,” “reference analyte meter,” and“reference analyte sensor” as used herein are broad terms and are to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and furthermore refer without limitation to a device thatmeasures a concentration of an analyte and can be used as a referencefor the continuous analyte sensor, for example a self-monitoring bloodglucose meter (SMBG) can be used as a reference for a continuous glucosesensor for comparison, calibration, and the like.

The term “sensing membrane” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to a permeable orsemi-permeable membrane that can be comprised of two or more domains andis typically constructed of materials of a few microns thickness ormore, which are permeable to oxygen and may or may not be permeable toglucose. In one example, the sensing membrane comprises an immobilizedglucose oxidase enzyme, which enables an electrochemical reaction tooccur to measure a concentration of glucose.

The term “physiologically feasible” as used herein is a broad term andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and furthermore refers without limitation to thephysiological parameters obtained from continuous studies of glucosedata in humans and/or animals. For example, a maximal sustained rate ofchange of glucose in humans of about 4 to 5 mg/dL/min and a maximumacceleration of the rate of change of about 0.1 to 0.2 mg/dL/min/min aredeemed physiologically feasible limits. Values outside of these limitswould be considered non-physiological and likely a result of signalerror, for example. As another example, the rate of change of glucose islowest at the maxima and minima of the daily glucose range, which arethe areas of greatest risk in patient treatment, thus a physiologicallyfeasible rate of change can be set at the maxima and minima based oncontinuous studies of glucose data. As a further example, it has beenobserved that the best solution for the shape of the curve at any pointalong glucose signal data stream over a certain time period (e.g., about20 to 30 minutes) is a straight line, which can be used to setphysiological limits.

The term “ischemia” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to local and temporary deficiencyof blood supply due to obstruction of circulation to a part (e.g.,sensor). Ischemia can be caused by mechanical obstruction (e.g.,arterial narrowing or disruption) of the blood supply, for example.

The term “system noise” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to unwantedelectronic or diffusion-related noise which can include Gaussian,motion-related, flicker, kinetic, or other white noise, for example.

The terms “noise,” “noise event(s),” “noise episode(s),” “signalartifact(s),” “signal artifact event(s),” and “signal artifactepisode(s)” as used herein are broad terms and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andfurthermore refer without limitation to signal noise that is caused bysubstantially non-glucose related, such as interfering species, macro-or micro-motion, ischemia, pH changes, temperature changes, pressure,stress, or even unknown sources of mechanical, electrical and/orbiochemical noise for example. In some embodiments, signal artifacts aretransient and characterized by a higher amplitude than system noise, anddescribed as “transient non-glucose related signal artifact(s) that havea higher amplitude than system noise.” In some embodiments, noise iscaused by rate-limiting (or rate-increasing) phenomena. In somecircumstances, the source of the noise is unknown.

The terms “constant noise” and “constant background” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to thecomponent of the noise signal that remains relatively constant overtime. In some embodiments, constant noise may be referred to as“background” or “baseline.” For example, certain electroactive compoundsfound in the human body are relatively constant factors (e.g., baselineof the host's physiology). In some circumstances, constant backgroundnoise can slowly drift over time (e.g., increase or decrease), howeverthis drift need not adversely affect the accuracy of a sensor, forexample, because a sensor can be calibrated and re-calibrated and/or thedrift measured and compensated for.

The terms “non-constant noise,” “non-constant background,” “noiseevent(s),” “noise episode(s),” “signal artifact(s),” “signal artifactevent(s),” and “signal artifact episode(s)” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to acomponent of the background signal that is relatively non-constant, forexample, transient and/or intermittent. For example, certainelectroactive compounds, are relatively non-constant due to the host'singestion, metabolism, wound healing, and other mechanical, chemicaland/or biochemical factors), which create intermittent (e.g.,non-constant) “noise” on the sensor signal that can be difficult to“calibrate out” using a standard calibration equations (e.g., becausethe background of the signal does not remain constant).

The terms “low noise” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to noise that substantiallydecreases signal amplitude.

The terms “high noise” and “high spikes” as used herein are broad termsand are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and furthermore refer without limitation to noisethat substantially increases signal amplitude.

The term “frequency content” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to the spectraldensity, including the frequencies contained within a signal and theirpower.

The term “spectral density” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to power spectraldensity of a given bandwidth of electromagnetic radiation is the totalpower in this bandwidth divided by the specified bandwidth. Spectraldensity is usually expressed in Watts per Hertz (W/Hz).

The term “chronoamperometry” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to anelectrochemical measuring technique used for electrochemical analysis orfor the determination of the kinetics and mechanism of electrodereactions. A fast-rising potential pulse is enforced on the working (orreference) electrode of an electrochemical cell and the current flowingthrough this electrode is measured as a function of time.

The term “pulsed amperometric detection” as used herein is a broad termand is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and furthermore refers without limitation to anelectrochemical flow cell and a controller, which applies the potentialsand monitors current generated by the electrochemical reactions. Thecell can include one or multiple working electrodes at different appliedpotentials. Multiple electrodes can be arranged so that they face thechromatographic flow independently (parallel configuration), orsequentially (series configuration).

The term “linear regression” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to finding a line inwhich a set of data has a minimal measurement from that line. Byproductsof this algorithm include a slope, a y-intercept, and an R-Squared valuethat determine how well the measurement data fits the line.

The term “non-linear regression” as used herein is a broad term and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to fitting a set ofdata to describe the relationship between a response variable and one ormore explanatory variables in a non-linear fashion.

The term “mean” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the sum of the observationsdivided by the number of observations.

The term “trimmed mean” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to a mean takenafter extreme values in the tails of a variable (e.g., highs and lows)are eliminated or reduced (e.g., “trimmed”). The trimmed meancompensates for sensitivities to extreme values by dropping a certainpercentage of values on the tails. For example, the 50% trimmed mean isthe mean of the values between the upper and lower quartiles. The 90%trimmed mean is the mean of the values after truncating the lowest andhighest 5% of the values. In one example, two highest and two lowestmeasurements are removed from a data set and then the remainingmeasurements are averaged.

The term “non-recursive filter” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to an equation thatuses moving averages as inputs and outputs.

The terms “recursive filter” and “auto-regressive algorithm” as usedherein are broad terms and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and are not to belimited to a special or customized meaning), and furthermore referwithout limitation to an equation in which includes previous averagesare part of the next filtered output. More particularly, the generationof a series of observations whereby the value of each observation ispartly dependent on the values of those that have immediately precededit. One example is a regression structure in which lagged responsevalues assume the role of the independent variables.

The term “signal estimation algorithm factors” as used herein is a broadterm and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and furthermore refers without limitation to one ormore algorithms that use historical and/or present signal data streamvalues to estimate unknown signal data stream values. For example,signal estimation algorithm factors can include one or more algorithms,such as linear or non-linear regression. As another example, signalestimation algorithm factors can include one or more sets ofcoefficients that can be applied to one algorithm.

The term “variation” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a divergence or amount ofchange from a point, line, or set of data. In one embodiment, estimatedanalyte values can have a variation including a range of values outsideof the estimated analyte values that represent a range of possibilitiesbased on known physiological patterns, for example.

The terms “physiological parameters” and “physiological boundaries” asused herein are broad terms and are to be given their ordinary andcustomary meaning to a person of ordinary skill in the art (and are notto be limited to a special or customized meaning), and furthermore referwithout limitation to the parameters obtained from continuous studies ofphysiological data in humans and/or animals. For example, a maximalsustained rate of change of glucose in humans of about 4 to 5 mg/dL/minand a maximum acceleration of the rate of change of about 0.1 to 0.2mg/dL/min² are deemed physiologically feasible limits; values outside ofthese limits would be considered non-physiological. As another example,the rate of change of glucose is lowest at the maxima and minima of thedaily glucose range, which are the areas of greatest risk in patienttreatment, thus a physiologically feasible rate of change can be set atthe maxima and minima based on continuous studies of glucose data. As afurther example, it has been observed that the best solution for theshape of the curve at any point along glucose signal data stream over acertain time period (for example, about 20 to 30 minutes) is a straightline, which can be used to set physiological limits. These terms arebroad enough to include physiological parameters for any analyte.

The term “measured analyte values” as used herein is a broad term and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to an analyte valueor set of analyte values for a time period for which analyte data hasbeen measured by an analyte sensor. The term is broad enough to includedata from the analyte sensor before or after data processing in thesensor and/or receiver (for example, data smoothing, calibration, andthe like).

The term “estimated analyte values” as used herein is a broad term andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and furthermore refers without limitation to ananalyte value or set of analyte values, which have been algorithmicallyextrapolated from measured analyte values.

The terms “interferants” and “interfering species” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto effects and/or species that interfere with the measurement of ananalyte of interest in a sensor to produce a signal that does notaccurately represent the analyte concentration. In one example of anelectrochemical sensor, interfering species are compounds with anoxidation potential that overlap that of the analyte to be measured,thereby producing a false positive signal.

As employed herein, the following abbreviations apply: Eq and Eqs(equivalents); mEq (milliequivalents); M (molar); mM (millimolar) μM(micromolar); N (Normal); mol (moles); mmol (millimoles); μmol(micromoles); nmol (nanomoles); g (grams); mg (milligrams); μg(micrograms); Kg (kilograms); L (liters); mL (milliliters); dL(deciliters); μL (microliters); cm (centimeters); mm (millimeters); μm(micrometers); nm (nanometers); h and hr (hours); min. (minutes); s andsec. (seconds); ° C. (degrees Centigrade).

Overview/General Description of System

The glucose sensor can use any system or method to provide a data streamindicative of the concentration of glucose in a host. The data stream istypically a raw data signal that is transformed to provide a usefulvalue of glucose to a user, such as a patient or doctor, who may beusing the sensor. Faults may occur, however, which may be detectable byanalysis of the signal, analysis of the clinical context, or both. Suchfaults require discrimination to distinguish the same from actualmeasured signal behavior, as well as for responsive signal processing,which can vary according to the fault. Accordingly, appropriate faultdiscrimination and responsive processing techniques are employed.

Glucose Sensor

The glucose sensor can be any device capable of measuring theconcentration of glucose. One exemplary embodiment is described below,which utilizes an implantable glucose sensor. However, it should beunderstood that the devices and methods described herein can be appliedto any device capable of detecting a concentration of glucose andproviding an output signal that represents the concentration of glucose.

Exemplary embodiments disclosed herein relate to the use of a glucosesensor that measures a concentration of glucose or a substanceindicative of the concentration or presence of another analyte. In someembodiments, the glucose sensor is a continuous device, for example asubcutaneous, transdermal, transcutaneous, non-invasive, intraocularand/or intravascular (e.g., intravenous) device. In some embodiments,the device can analyze a plurality of intermittent blood samples. Theglucose sensor can use any method of glucose measurement, includingenzymatic, chemical, physical, electrochemical, optical, optochemical,fluorescence-based, spectrophotometric, spectroscopic (e.g., opticalabsorption spectroscopy, Raman spectroscopy, etc.), polarimetric,calorimetric, iontophoretic, radiometric, and the like.

The glucose sensor can use any known detection method, includinginvasive, minimally invasive, and non-invasive sensing techniques, toprovide a data stream indicative of the concentration of the analyte ina host. The data stream is typically a raw data signal that is used toprovide a useful value of the analyte to a user, such as a patient orhealth care professional (e.g., doctor), who may be using the sensor.

Although much of the description and examples are drawn to a glucosesensor capable of measuring the concentration of glucose in a host, thesystems and methods of embodiments can be applied to any measurableanalyte, a list of appropriate analytes noted above. Some exemplaryembodiments described below utilize an implantable glucose sensor.However, it should be understood that the devices and methods describedherein can be applied to any device capable of detecting a concentrationof analyte and providing an output signal that represents theconcentration of the analyte.

In one preferred embodiment, the analyte sensor is an implantableglucose sensor, such as described with reference to U.S. Pat. No.6,001,067 and U.S. Patent Publication No. US-2005-0027463-A1. In anotherpreferred embodiment, the analyte sensor is a transcutaneous glucosesensor, such as described with reference to U.S. Patent Publication No.US-2006-0020187-A1. In still other embodiments, the sensor is configuredto be implanted in a host vessel or extracorporeally, such as isdescribed in U.S. Patent Publication No. US-2007-0027385-A1, U.S. PatentPublication No. US-2008-0119703-A1, U.S. Patent Publication No.US-2008-0108942-A1, and U.S. Patent Publication No. US-2007-0197890-A1.In one alternative embodiment, the continuous glucose sensor comprises atranscutaneous sensor such as described in U.S. Pat. No. 6,565,509 toSay et al., for example. In another alternative embodiment, thecontinuous glucose sensor comprises a subcutaneous sensor such asdescribed with reference to U.S. Pat. No. 6,579,690 to Bonnecaze et al.or U.S. Pat. No. 6,484,046 to Say et al., for example. In anotheralternative embodiment, the continuous glucose sensor comprises arefillable subcutaneous sensor such as described with reference to U.S.Pat. No. 6,512,939 to Colvin et al., for example. In another alternativeembodiment, the continuous glucose sensor comprises an intravascularsensor such as described with reference to U.S. Pat. No. 6,477,395 toSchulman et al., for example. In another alternative embodiment, thecontinuous glucose sensor comprises an intravascular sensor such asdescribed with reference to U.S. Pat. No. 6,424,847 to Mastrototaro etal.

The following description and examples described the present embodimentswith reference to the drawings. In the drawings, reference numbers labelelements of the present embodiments. These reference numbers arereproduced below in connection with the discussion of the correspondingdrawing features.

Specific Description of System

FIG. 1A is an exploded perspective view of one exemplary embodimentcomprising an implantable glucose sensor 10 that utilizes amperometricelectrochemical sensor technology to measure glucose concentration. Inthis exemplary embodiment, a body 12 and head 14 house the electrodes 16and sensor electronics, which are described in more detail below withreference to FIG. 2. Three electrodes 16 are operably connected to thesensor electronics (FIG. 2) and are covered by a sensing membrane 17 anda biointerface membrane 18, which are attached by a clip 19.

In one embodiment, the three electrodes 16, which protrude through thehead 14, include a platinum working electrode, a platinum counterelectrode, and a silver/silver chloride reference electrode. The topends of the electrodes are in contact with an electrolyte phase (notshown), which is a free-flowing fluid phase disposed between the sensingmembrane 17 and the electrodes 16. The sensing membrane 17 includes anenzyme, e.g., glucose oxidase, which covers the electrolyte phase. Thebiointerface membrane 18 covers the sensing membrane 17 and serves, atleast in part, to protect the sensor 10 from external forces that canresult in environmental stress cracking of the sensing membrane 17.

In the illustrated embodiment, the counter electrode is provided tobalance the current generated by the species being measured at theworking electrode. In the case of a glucose oxidase based glucosesensor, the species being measured at the working electrode is H₂O₂.Glucose oxidase catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate according to the following reaction:

Glucose+O₂→Gluconate+H₂O₂

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂. Oxidation of H₂O₂ by the working electrodeis balanced by reduction of ambient oxygen, enzyme generated H₂O₂, orother reducible species at the counter electrode. The H₂O₂ produced fromthe glucose oxidase reaction further reacts at the surface of workingelectrode and produces two protons (2H⁺), two electrons (2e⁻), and oneoxygen molecule (O₂).

FIGS. 1B-1C illustrate one exemplary embodiment of an in vivo portion ofa continuous analyte sensor 100, which includes an elongated conductivebody 102. The elongated conductive body 102 includes a core 110 (seeFIG. 1B) and a first layer 112 at least partially surrounding the core.The first layer includes a working electrode (e.g., located in window106) and a membrane 108 located over the working electrode configuredand arranged for multi-axis bending. In some embodiments, the core andfirst layer can be of a single material (e.g., platinum). In someembodiments, the elongated conductive body is a composite of at leasttwo materials, such as a composite of two conductive materials, or acomposite of at least one conductive material and at least onenon-conductive material. In some embodiments, the elongated conductivebody comprises a plurality of layers. In certain embodiments, there areat least two concentric (e.g., annular) layers, such as a core formed ofa first material and a first layer formed of a second material. However,additional layers can be included in some embodiments. In someembodiments, the layers are coaxial.

The elongated conductive body may be long and thin, yet flexible andstrong. For example, in some embodiments, the smallest dimension of theelongated conductive body is less than about 0.1 inches, 0.075 inches,0.05 inches, 0.025 inches, 0.01 inches, 0.004 inches, or 0.002 inches.While the elongated conductive body is illustrated in FIGS. 1B-1C ashaving a circular cross-section, in other embodiments the cross-sectionof the elongated conductive body can be ovoid, rectangular, triangular,polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-Shaped,irregular, or the like. In one embodiment, a conductive wire electrodeis employed as a core. To such a clad electrode, two additionalconducting layers may be added (e.g., with intervening insulating layersprovided for electrical isolation). The conductive layers can becomprised of any suitable material. In certain embodiments, it can bedesirable to employ a conductive layer comprising conductive particles(i.e., particles of a conductive material) in a polymer or other binder.

In certain embodiments, the materials used to form the elongatedconductive body (e.g., stainless steel, titanium, tantalum, platinum,platinum-iridium, iridium, certain polymers, and/or the like) can bestrong and hard, and therefore are resistant to breakage. For example,in some embodiments, the ultimate tensile strength of the elongatedconductive body is from about 80 kPsi to about 500 kPsi. In anotherexample, in some embodiments, the Young's modulus of the elongatedconductive body is from about 160 GPa to about 220 GPa. In still anotherexample, in some embodiments, the yield strength of the elongatedconductive body is from about 60 kPsi to about 2200 MPa. In someembodiments, the sensor's small diameter provides (e.g., imparts,enables) flexibility to these materials, and therefore to the sensor asa whole. Thus, the sensor can withstand repeated forces applied to it bysurrounding tissue. In some embodiments, the fatigue life of the sensoris at least 1,000 cycles of flexing of from about 28° to about 110° at abend radius of about 0.125-inches.

In addition to providing structural support, resiliency and flexibility,in some embodiments, the core 110 (or a component thereof) provideselectrical conduction for an electrical signal from the workingelectrode to sensor electronics (FIG. 2), which are described elsewhereherein. In some embodiments, the core 110 comprises a conductivematerial, such as stainless steel, titanium, tantalum, a conductivepolymer, and/or the like. However, in other embodiments, the core isformed from a non-conductive material, such as a non-conductive polymer.In yet other embodiments, the core comprises a plurality of layers ofmaterials. For example, in one embodiment the core includes an innercore and an outer core. In a further embodiment, the inner core isformed of a first conductive material and the outer core is formed of asecond conductive material. For example, in some embodiments, the firstconductive material is stainless steel, titanium, tantalum, a conductivepolymer, an alloy, and/or the like, and the second conductive materialis conductive material selected to provide electrical conduction betweenthe core and the first layer, and/or to attach the first layer to thecore (e.g., if the first layer is formed of a material that does notattach well to the core material). In another embodiment, the core isformed of a non-conductive material (e.g., a non-conductive metal and/ora non-conductive polymer) and the first layer is a conductive material,such as stainless steel, titanium, tantalum, a conductive polymer,and/or the like. The core and the first layer can be of a single (orsame) material, e.g., platinum. One skilled in the art appreciates thatadditional configurations are possible.

Referring again to FIGS. 1B-1C, in some embodiments, the first layer 112is formed of a conductive material. The working electrode is an exposedportion of the surface of the first layer. Accordingly, the first layeris formed of a material configured to provide a suitable electroactivesurface for the working electrode, a material such as but not limited toplatinum, platinum-iridium, gold, palladium, iridium, graphite, carbon,a conductive polymer, an alloy and/or the like.

As illustrated in FIGS. 1B-1C, a second layer 104 surrounds a least aportion of the first layer 112, thereby defining the boundaries of theworking electrode. In some embodiments, the second layer 104 serves asan insulator and is formed of an insulating material, such as polyimide,polyurethane, parylene, or any other known insulating materials. Forexample, in one embodiment the second layer is disposed on the firstlayer and configured such that the working electrode is exposed viawindow 106. In another embodiment, an elongated conductive body,including the core, the first layer and the second layer, is provided,and the working electrode is exposed (i.e., formed) by removing aportion of the second layer, thereby forming the window 106 throughwhich the electroactive surface of the working electrode (e.g., theexposed surface of the first layer) is exposed. In some embodiments, theworking electrode is exposed by (e.g., window 106 is formed by) removinga portion of the second and (optionally) third layers. Removal ofcoating materials from one or more layers of elongated conductive body(e.g., to expose the electroactive surface of the working electrode) canbe performed by hand, excimer lasing, chemical etching, laser ablation,grit-blasting, or the like.

In some embodiments, the sensor further comprises a third layer 114comprising a conductive material. In further embodiments, the thirdlayer may comprise a reference electrode, which may be formed of asilver-containing material that is applied onto the second layer (e.g.,an insulator). The silver-containing material may include any of avariety of materials and be in various forms, such as, Ag/AgCl-polymerpastes, paints, polymer-based conducting mixture, and/or inks that arecommercially available, for example. The third layer can be processedusing a pasting/dipping/coating step, for example, using a die-metereddip coating process. In one exemplary embodiment, an Ag/AgCl polymerpaste is applied to an elongated body by dip-coating the body (e.g.,using a meniscus coating technique) and then drawing the body through adie to meter the coating to a precise thickness. In some embodiments,multiple coating steps are used to build up the coating to apredetermined thickness. Such a drawing method can be utilized forforming one or more of the electrodes in the device depicted in FIG. 1B.

In some embodiments, the silver grain in the Ag/AgCl solution or pastecan have an average particle size corresponding to a maximum particledimension that is less than about 100 microns, or less than about 50microns, or less than about 30 microns, or less than about 20 microns,or less than about 10 microns, or less than about 5 microns. The silverchloride grain in the Ag/AgCl solution or paste can have an averageparticle size corresponding to a maximum particle dimension that is lessthan about 100 microns, or less than about 80 microns, or less thanabout 60 microns, or less than about 50 microns, or less than about 20microns, or less than about 10 microns. The silver grain and the silverchloride grain may be incorporated at a ratio of the silver chloridegrain:silver grain of from about 0.01:1 to 2:1 by weight, or from about0.1:1 to 1:1. The silver grains and the silver chloride grains are thenmixed with a carrier (e.g., a polyurethane) to form a solution or paste.In certain embodiments, the Ag/AgCl component form from about 10% toabout 65% by weight of the total Ag/AgCl solution or paste, or fromabout 20% to about 50%, or from about 23% to about 37%. In someembodiments, the Ag/AgCl solution or paste has a viscosity (underambient conditions) that is from about 1 to about 500 centipoise, orfrom about 10 to about 300 centipoise, of from about 50 to about 150centipoise.

In some embodiments, Ag/AgCl particles are mixed into a polymer, such aspolyurethane, polyimide, or the like, to form the silver-containingmaterial for the reference electrode. In some embodiments, the thirdlayer is cured, for example, by using an oven or other curing process.In some embodiments, a covering of fluid-permeable polymer withconductive particles (e.g., carbon particles) therein is applied overthe reference electrode and/or third layer. A layer of insulatingmaterial is located over a portion of the silver-containing material, insome embodiments.

In some embodiments, the elongated conductive body further comprises oneor more intermediate layers located between the core and the firstlayer. For example, in some embodiments, the intermediate layer is aninsulator, a conductor, a polymer, and/or an adhesive.

It is contemplated that the ratio between the thickness of the Ag/AgCllayer and the thickness of an insulator (e.g., polyurethane orpolyimide) layer can be controlled, so as to allow for a certain errormargin (e.g., an error margin resulting from the etching process) thatwould not result in a defective sensor (e.g., due to a defect resultingfrom an etching process that cuts into a depth more than intended,thereby unintentionally exposing an electroactive surface). This ratiomay be different depending on the type of etching process used, whetherit is laser ablation, grit blasting, chemical etching, or some otheretching method. In one embodiment in which laser ablation is performedto remove a Ag/AgCl layer and a polyurethane layer, the ratio of thethickness of the Ag/AgCl layer and the thickness of the polyurethanelayer can be from about 1:5 to about 1:1, or from about 1:3 to about1:2.

In certain embodiment, the core comprises a non-conductive polymer andthe first layer comprises a conductive material. Such a sensorconfiguration can sometimes provide reduced material costs, in that itreplaces a typically expensive material with an inexpensive material.For example, in some embodiments, the core is formed of a non-conductivepolymer, such as, a nylon or polyester filament, string or cord, whichcan be coated and/or plated with a conductive material, such asplatinum, platinum-iridium, gold, palladium, iridium, graphite, carbon,a conductive polymer, and allows or combinations thereof.

As illustrated in FIG. 1C, the sensor also includes a membrane 108covering at least a portion of the working electrode.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting, or the like, to expose the electroactive surfaces.Alternatively, a portion of the electrode can be masked prior todepositing the insulator in order to maintain an exposed electroactivesurface area.

In some embodiments, a radial window is formed through the insulatingmaterial to expose a circumferential electroactive surface of theworking electrode. Additionally, sections of electroactive surface ofthe reference electrode are exposed. For example, the sections ofelectroactive surface can be masked during deposition of an outerinsulating layer or etched after deposition of an outer insulatinglayer. In some applications, cellular attack or migration of cells tothe sensor can cause reduced sensitivity or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g. as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and an additional working electrode(e.g. an electrode which can be used to generate oxygen, which isconfigured as a baseline subtracting electrode, or which is configuredfor measuring additional analytes). U.S. Pat. No. 7,081,195, U.S. PatentPublication No. US-2005-0143635-A1 and U.S. Patent Publication No.US-2007-0027385-A1, each of which are incorporated herein by reference,describe some systems and methods for implementing and using additionalworking, counter, and reference electrodes. In one implementationwherein the sensor comprises two working electrodes, the two workingelectrodes are juxtapositioned, around which the reference electrode isdisposed (e.g. helically wound). In some embodiments wherein two or moreworking electrodes are provided, the working electrodes can be formed ina double-, triple-, quad-, etc. helix configuration along the length ofthe sensor (for example, surrounding a reference electrode, insulatedrod, or other support structure). The resulting electrode system can beconfigured with an appropriate membrane system, wherein the firstworking electrode is configured to measure a first signal comprisingglucose and baseline signals, and the additional working electrode isconfigured to measure a baseline signal consisting of the baselinesignal only. In these embodiments, the second working electrode may beconfigured to be substantially similar to the first working electrode,but without an enzyme disposed thereon. In this way, the baseline signalcan be determined and subtracted from the first signal to generate adifference signal, i.e., a glucose-only signal that is substantially notsubject to fluctuations in the baseline or interfering species on thesignal, such as described in U.S. Patent Publication No.US-2005-0143635-A1, U.S. Patent Publication No. US-2007-0027385-A1, andU.S. Patent Publication No. US-2007-0213611-A1, and U.S. PatentPublication No. US-2008-0083617-A1, which are incorporated herein byreference in their entirety.

It has been found that in some electrode systems involving two workingelectrodes, i.e., in some dual-electrode systems, the working electrodesmay sometimes be slightly different from each other. For instance, twoworking electrodes, even when manufactured from a single facility mayslightly differ in thickness or permeability because of the electrodes'high sensitivity to environmental conditions (e.g. temperature,humidity) during fabrication. Accordingly, the working electrodes of adual-electrode system may sometimes have varying diffusion, membranethickness, and diffusion characteristics. As a result, theabove-described difference signal (i.e., a glucose-only signal,generated from subtracting the baseline signal from the first signal)may not be completely accurate. To mitigate this, it is contemplatedthat in some dual-electrode systems, both working electrodes may befabricated with one or more membranes that each includes a bioprotectivelayer, which is described in more detail elsewhere herein.

It is contemplated that the sensing region may include any of a varietyof electrode configurations. For example, in some embodiments, inaddition to one or more glucose-measuring working electrodes, thesensing region may also include a reference electrode or otherelectrodes associated with the working electrode. In these particularembodiments, the sensing region may also include a separate reference orcounter electrode associated with one or more optional auxiliary workingelectrodes. In other embodiments, the sensing region may include aglucose-measuring working electrode, an auxiliary working electrode, twocounter electrodes (one for each working electrode), and one sharedreference electrode. In yet other embodiments, the sensing region mayinclude a glucose-measuring working electrode, an auxiliary workingelectrode, two reference electrodes, and one shared counter electrode.

U.S. Patent Publication No. US-2008-0119703-A1 and U.S. PatentPublication No. US-2005-0245799-A1 describe additional configurationsfor using the continuous sensor in different body locations. In someembodiments, the sensor is configured for transcutaneous implantation inthe host. In alternative embodiments, the sensor is configured forinsertion into the circulatory system, such as a peripheral vein orartery. However, in other embodiments, the sensor is configured forinsertion into the central circulatory system, such as but not limitedto the vena cava. In still other embodiments, the sensor can be placedin an extracorporeal circulation system, such as but not limited to anintravascular access device providing extracorporeal access to a bloodvessel, an intravenous fluid infusion system, an extracorporeal bloodchemistry analysis device, a dialysis machine, a heart-lung machine(i.e., a device used to provide blood circulation and oxygenation whilethe heart is stopped during heart surgery), etc. In still otherembodiments, the sensor can be configured to be wholly implantable, asdescribed in U.S. Pat. No. 6,001,067.

FIG. 2 is a block diagram that illustrates one possible configuration ofthe sensor electronics in one embodiment. In this embodiment, apotentiostat 20 is shown, which is operatively connected to an electrodesystem and provides a voltage to the electrodes, which biases the sensorto enable measurement of a current value indicative of the analyteconcentration in the host (also referred to as the analog portion). Insome embodiments, the potentiostat includes a resistor (not shown) thattranslates the current into voltage. In some alternative embodiments, acurrent to frequency converter is provided that is configured tocontinuously integrate the measured current, for example, using a chargecounting device. In the illustrated embodiment, an A/D converter 21digitizes the analog signal into “counts” for processing. Accordingly,the resulting raw data stream in counts is directly related to thecurrent measured by the potentiostat 20.

A processor module 22 is the central control unit that controls theprocessing of the sensor electronics. In some embodiments, the processormodule includes a microprocessor, however a computer system other than amicroprocessor can be used to process data as described herein, forexample an ASIC can be used for some or all of the sensor's centralprocessing. The processor typically provides semi-permanent storage ofdata, for example, storing data such as sensor identifier (ID) andprogramming to process data streams (for example, programming for datasmoothing and/or replacement of signal artifacts such as is described inmore detail elsewhere herein). The processor additionally can be usedfor the system's cache memory, for example for temporarily storingrecent sensor data. In some embodiments, the processor module comprisesmemory storage components such as various types of ROM, RAM, flashmemory, and the like. In one exemplary embodiment, ROM 23 providessemi-permanent storage of data, for example, storing data such as sensoridentifier (ID) and programming to process data streams (e.g.,programming for signal artifacts detection and/or replacement such asdescribed elsewhere herein). In one exemplary embodiment, RAM 24 can beused for the system's cache memory, for example for temporarily storingrecent sensor data.

In some embodiments, the processor module comprises a digital filter,for example, an IIR or FIR filter, configured to smooth the raw datastream from the A/D converter. Generally, digital filters are programmedto filter data sampled at a predetermined time interval (also referredto as a sample rate). In some embodiments, wherein the potentiostat isconfigured to measure the analyte at discrete time intervals, these timeintervals determine the sample rate of the digital filter. In somealternative embodiments, wherein the potentiostat is configured tocontinuously measure the analyte, for example, using acurrent-to-frequency converter, the processor module can be programmedto request a digital value from the A/D converter at a predeterminedtime interval, also referred to as the acquisition time. In thesealternative embodiments, the values obtained by the processor areadvantageously averaged over the acquisition time due the continuity ofthe current measurement. Accordingly, the acquisition time determinesthe sample rate of the digital filter. In preferred embodiments, theprocessor module is configured with a programmable acquisition time,namely, the predetermined time interval for requesting the digital valuefrom the A/D converter is programmable by a user within the digitalcircuitry of the processor module. An acquisition time of from about 2seconds to about 512 seconds is preferred; however any acquisition timecan be programmed into the processor module. A programmable acquisitiontime is advantageous in optimizing noise filtration, time lag, andprocessing/battery power.

Preferably, the processor module is configured to build the data packetfor transmission to an outside source, for example, an RF transmissionto a receiver as described in more detail below. Generally, the datapacket comprises a plurality of bits that can include a sensor ID code,raw data, filtered data, and/or error detection or correction. Theprocessor module can be configured to transmit any combination of rawand/or filtered data.

A battery 25 is operatively connected to the processor 22 and providesthe necessary power for the sensor (e.g., 100). In one embodiment, thebattery is a Lithium Manganese Dioxide battery, however anyappropriately sized and powered battery can be used (e.g., AAA,Nickel-cadmium, Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride,Lithium-ion, Zinc-air, Zinc-mercury oxide, Silver-zinc, orhermetically-sealed). In some embodiments the battery is rechargeable.In some embodiments, a plurality of batteries can be used to power thesystem. In yet other embodiments, the receiver can be transcutaneouslypowered via an inductive coupling, for example. A Quartz Crystal 26 isoperatively connected to the processor 22 and maintains system time forthe computer system as a whole.

An RF module, (e.g., an RF Transceiver) 27 is operably connected to theprocessor 22 and transmits the sensor data from the sensor (e.g., 100)to a receiver (see FIGS. 3 and 4). Although an RF transceiver is shownhere, some other embodiments can include a wired rather than wirelessconnection to the receiver. A second quartz crystal 28 provides thesystem time for synchronizing the data transmissions from the RFtransceiver. It is noted that the transceiver 27 can be substituted witha transmitter in other embodiments. In some alternative embodiments,however, other mechanisms, such as optical, infrared radiation (IR),ultrasonic, and the like, can be used to transmit and/or receive data.

In some embodiments, a Signal Artifacts Detector 29 is provided thatincludes one or more of the following: an oxygen detector 29 a, a pHdetector 29 b, a temperature detector 29 c, and a pressure/stressdetector 29 d, which is described in more detail with reference tosignal artifacts and faults/errors detection and discrimination. It isnoted that in some embodiments the signal artifacts detector 29 is aseparate entity (e.g., temperature detector) operatively connected tothe processor, while in other embodiments, the signal artifacts detectoris a part of the processor and utilizes readings from the electrodes,for example, to detect signal faults and artifacts. Although the abovedescription includes some embodiments in which all discrimination occurswithin the sensor, other embodiments provide for systems and methods fordetecting signal faults in the sensor and/or receiver electronics (e.g.,processor module) as described in more detail elsewhere herein.

Receiver

FIGS. 3A to 3D are schematic views of a receiver 30 includingrepresentations of estimated glucose values on its user interface infirst, second, third, and fourth embodiments, respectively. The receiver30 comprises systems to receive, process, and display sensor data fromthe glucose sensor (e.g., 100), such as described herein. Particularly,the receiver 30 can be a mobile phone type device, for example, andcomprise a user interface that has a physical button 32 and a displayscreen 34, as well as one or more input/output (I/O) devices, such asone or more buttons 55 and/or switches 57, which when activated orclicked perform one or more functions. In the illustrated embodiment,the electronic device is a smartphone, and the display 34 comprises atouchscreen, which also functions as an I/O device. In some embodiments,the user interface can also include a keyboard, a speaker, and avibrator. The functions of the receiver or smart phone can also beimplemented as functions within an application running on a tabletcomputer, or like device. In other embodiments, the receiver maycomprise a device or devices other than a smartphone, such as asmartwatch, a tablet computer, a mini-tablet computer, a handheldpersonal digital assistant (PDA), a game console, a multimedia player, awearable device, such as those described above, a screen in anautomobile or other vehicle, a dedicated receiver device, etc.

FIG. 3A illustrates a first embodiment where the receiver 30 shows anumeric representation of the estimated glucose value on its userinterface. FIG. 3B illustrates a second embodiment where the receiver 30shows an estimated glucose value and approximately one hour ofhistorical trend data on its user interface. FIG. 3C illustrates a thirdembodiment where the receiver 30 shows an estimated glucose value andapproximately three hours of historical trend data on its userinterface. FIG. 3D illustrates a fourth embodiment where the receiver 30shows an estimated glucose value and approximately nine hours ofhistorical trend data on its user interface. In some embodiments, a usercan toggle through some or all of the screens shown in FIGS. 3A to 3Dusing a physical button or a button implemented on a touch screeninterface. In some embodiments, the user will be able to interactivelyselect the type of output displayed on their user interface. In otherembodiments, the sensor output can have alternative configurations.

FIG. 4 is a block diagram that illustrates one possible configuration ofthe receiver, e.g., a smart phone, electronics. It is noted that thereceiver can comprise a configuration such as described with referenceto FIGS. 3A to 3D, above. Alternatively, the receiver can comprise otherconfigurations, including a desktop computer, laptop computer, apersonal digital assistant (PDA), a server (local or remote to thereceiver), and the like. In some embodiments, the receiver can beadapted to connect (via wired or wireless connection) to a desktopcomputer, laptop computer, PDA, server (local or remote to thereceiver), and the like, in order to download data from the receiver. Insome alternative embodiments, the receiver and/or receiver electronicscan be housed within or directly connected to the sensor (e.g., 100) ina manner that allows sensor and receiver electronics to work directlytogether and/or share data processing resources. Accordingly, thereceiver's electronics (or any combination of sensor and/or receiverelectronics) can be generally referred to as a “computer system.”

A quartz crystal 40 is operatively connected to an RF transceiver 41that together function to receive and synchronize data streams (e.g.,raw data streams transmitted from the RF transceiver). Once received, aprocessor 42 processes the signals, such as described below.

The processor 42, also referred to as the processor module, is thecentral control unit that performs the processing, such as storing data,analyzing data streams, calibrating analyte sensor data, predictinganalyte values, comparing predicted analyte values with correspondingmeasured analyte values, analyzing a variation of predicted analytevalues, downloading data, and controlling the user interface byproviding analyte values, prompts, messages, warnings, alarms, and thelike. The processor includes hardware and software that performs theprocessing described herein, for example flash memory provides permanentor semi-permanent storage of data, storing data such as sensor ID,receiver ID, and programming to process data streams (for example,programming for performing prediction and other algorithms describedelsewhere herein) and random access memory (RAM) stores the system'scache memory and is helpful in data processing.

In one exemplary embodiment, the processor is a microprocessor thatprovides the processing, such as calibration algorithms stored within aROM 43. The ROM 43 is operatively connected to the processor 42 andprovides semi-permanent storage of data, storing data such as receiverID and programming to process data streams (e.g., programming forperforming calibration and other algorithms described elsewhere herein).In this exemplary embodiment, a RAM 44 is used for the system's cachememory and is helpful in data processing.

A battery 45 is operatively connected to the processor 42 and providespower for the receiver. In one embodiment, the battery is a standard AAAalkaline battery, however any appropriately sized and powered batterycan be used. In some embodiments, a plurality of batteries can be usedto power the system. A quartz crystal 46 is operatively connected to theprocessor 42 and maintains system time for the computer system as awhole.

A user interface 47 comprises a keyboard 2, speaker 3, vibrator 4,backlight 5, liquid crystal display (LCD 6), and one or more buttons 7,which may be implemented as physical buttons or buttons on a touchscreeninterface. The components that comprise the user interface 47 providecontrols to interact with the user. The keyboard 2 can allow, forexample, input of user information about himself/herself, such asmealtime, exercise, insulin administration, and reference glucosevalues. The speaker 3 can provide, for example, audible signals oralerts for conditions such as present and/or predicted hyper- andhypoglycemic conditions. The vibrator 4 can provide, for example,tactile signals or alerts for reasons such as described with referenceto the speaker, above. The backlight 5 can be provided, for example, toaid the user in reading the LCD in low light conditions. The LCD 6 canbe provided, for example, to provide the user with visual data outputsuch as is illustrated in FIGS. 3A to 3D. The buttons 7 can provide fortoggle, menu selection, option selection, mode selection, and reset, forexample.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as requests forreference analyte values, therapy recommendations, deviation of themeasured analyte values from the predicted analyte values, and the like.Additionally, prompts can be displayed to guide the user throughcalibration or trouble-shooting of the calibration.

In some implementations, the continuous analyte sensor system includes aDexcom G4® Platinum glucose sensor and transmitter commerciallyavailable from Dexcom, Inc., for continuously monitoring a host'sglucose levels.

In some embodiments, the system may execute various applications, forexample, a CGM application, which may be downloaded to the receiver orother electronic device over the Internet and/or a cellular network, andthe like. Data for various applications may be shared between the deviceand one or more other devices/systems, and stored by cloud or networkstorage and/or on one or more other devices/systems. This CGMapplication may include a fault discrimination and responsive processingmodule and/or may include processing sufficient to operate faultdiscrimination and remediation functions and methods as described below.

Introduction to Fault Discrimination and Responsive Processing Based onData and Context

Referring to FIG. 5, a flowchart 50 illustrates a general methodaccording to present principles. The method generally involves receptionof a signal from a monitoring device, such as from an analyteconcentration monitor, e.g., a CGM (step 52). This signal may be “raw”,in the sense that the same represents a number of counts and on whichlittle or no significant processing has occurred. The method alsoinvolves reception of clinical context information (step 54), which isgenerally information about the patient environment and clinicalsetting. For example, for diabetes management, appropriate clinicalcontext information may include meals ingested, insulin delivered,patient exercise, patient temperature, clinical glucose value (asdistinguished from the raw signal value), and the like. Faults are thendetected based on the signal, the clinical context, or both, and one orboth may further play a role in responsive processing.

Appropriate fault discrimination is important in the prevention ofinaccurate clinical glucose values, especially as displayed to a user.Inaccurate values may cause the user to take inappropriate actions, theymay deteriorate the performance of predictive algorithms or closed loopalgorithms, and they deteriorate the user's trust of their CGM sensor.

In a method according to present principles, a fault is then detected,determined or discriminated (step 56), collectively “discriminated”. Thefault may be discriminated solely on the basis of the received signal,or on the basis of both the received signal and the received clinicalcontext. Responsive processing may then occur (step 58), and the samemay be based on the discriminated fault and on the clinical context asseparate variables or parameters, or on just the discriminated fault (inwhich the clinical context played a role in the discrimination). In aspecial case of the method, the received signal, or the received signaland clinical context data, may be employed to discriminate a category offault, and responsive processing may occur based on the category offault. Other special cases will also be understood. These generalprinciples are now described in greater detail, along with examples.

Received Signal and Clinical Context

As noted above, systems and methods according to present principlesgenerally base fault discrimination and responsive processing methods onone or more received signals, one of which is generally related to a rawsensor signal such as an analyte concentration, e.g., glucoseconcentration, as well as on data about a clinical context, e.g., otherphysiological data about the patient, data about the patient environment(activity level, patterns, time of day, and the like). Each of theseaspects is described in greater detail below.

Sensor Signal Analysis/Other Signals

FIG. 6 illustrates aspects of a received signal 62, as well as ways ofdiscriminating the signal. First, the fault discrimination andresponsive processing methods may be based on a raw signal 64, which ismeasured by the sensor electrode and is in the form of an uncalibratednumber of counts with respect to time.

Second, the methods may be based on a processed raw signal 66, but wherethe processing is unrelated or preliminary to determining the analyteconcentration value as used in a clinical value determination. In otherwords, the processing is unrelated or only preliminary to translatingthe raw signal counts into meaningful units for patient management,e.g., diabetes management, e.g., as a value expressed in mg/dL ormmol/L. Put yet another way, the processed raw signal is uncalibratedand by itself is not useful for clinical value determination.

The processing performed on the signal 66 is performed becauseaberrations can occur in the signal due to non-glucose relatedartifacts. Simple averaging or other processes cannot always grid thesignal of such artifacts without losing important glucose concentrationdata in the signal itself.

One example of signal processing unrelated to transformation of the rawsignal into a clinical value includes processing related to noisefiltering. Such processing results in a signal 68 in which noise hasbeen filtered out to a greater or lesser degree. Various aspects ofnoise filtering are described in greater detail below. Details ofparticular processing steps for noise filtering are provided in U.S.Pat. No. 8,260,393, issued Sep. 4, 2012, owned by the assignee of thepresent application and herein incorporated by reference in itsentirety.

For example, in a particular implementation of noise filtering,illustrated in FIGS. 6B-6D, filtering is performed differently atdifferent rates of change to achieve different levels of smoothness. Inmore detail, for a given received signal, a magnitude of noise withinthe signal is measured over a window of time, and then the rate ofchange for the signal is measured over a similar window of time. Whileit is possible to completely remove the noise error by filtering, anerror is created in doing so, the error being equal to the rate ofchange multiplied by the filtered delay. As it is preferable to presentsmooth data to users, a longest delay possible may be chosen for maximumsmoothness. In other words, the filter delay is chosen to be equal tothe noise magnitude divided by the rate of change. In this way, minimumerror is achieved with maximal smoothness. FIGS. 6B and 6C illustratetwo examples, having different rates of change but the same noisemagnitude. The resulting filter lengths are also illustrated. Thus, inone type of responsive processing, a filter delay is altered based on atleast one signal characteristic, such as a magnitude of noise, as wellas in some cases a rate of change of the signal.

In another implementation, and referring to FIG. 6D, thresholds may beset for a level of smoothing not based on accuracy of the signal butrather based on user perception of data quality. A characteristic of thesignal may be measured. In one case, a third derivative characteristic(i.e., “jerk”) has been shown to indicate signal quality as perceived byusers, and is a useful characteristic since it is easily measurable inreal time, particularly when sampling occurs frequently, e.g., every 30seconds. A set of signals with varying jerk levels may be displayed tousers, and users may select which signal they wish to see, e.g., whichdelivers the most informative data to that user. By monitoringselections, a determination may be made as to jerk levels that areacceptable or unacceptable to users. Even in such systems, some level ofminimum filtering may be performed to meet user expectations of signalsmoothness.

Besides filtering, other types of signal processing unrelated totransformation of the raw signal into a clinical value will also beunderstood.

The received signal 62, raw signal 64 or processed signal 66, is thenanalyzed to discriminate a fault therein, with or without the use ofclinical context information and/or other signals, and a result 72 isobtained which includes data about a fault on which responsiveprocessing may be based. Details of the analysis and discrimination arenow described. In general, an exemplary implementation may be to receivethe signal data and compare the same against fault discriminationcriteria, in order to determine or discriminate fault information.

Other signals 74 may be employed in the discrimination analysis, besidesthat of the received raw analyte (e.g., glucose) electrode signal. Suchother signals include those relating to temperature of the sensor andassociated electronics, impedance of the sensor and constituentcomponents, background noise encountered by the sensor, and the like.For example, and referring to FIG. 7, a graph 101 is illustrated havinga raw signal axis 105 and a temperature axis 107, plotted against time109. As temperature rises, one potential effect of the same is to causea gradual increase or decrease in the signal, this increase or decreaseunrelated to actual glucose levels. A raw data trace 113 is illustratedrepresenting an actual glucose value, e.g., in mg/dL, withouttemperature effects. A trace 115 is also illustrated, this tracerepresenting the raw data in the case of an elevated internal sensortemperature, the elevated temperature causing a gradual increase in thesignal (thus causing a separation in the traces). By establishing acorrelation between an elevated sensor temperature and an increasedsignal, the former can be used as an input in the discriminationanalysis.

As another example, the signal from other constituent sensors such asoxygen sensors may be employed in fault discrimination. For example, ifbecause of a compression fault (described in greater detail below), aglucose sensor signal is blocked, the compression fault should alsoblock the oxygen sensor. An example is shown by the graph 122 of FIG.8A, in which raw signal values are plotted on axis 124 versus time onaxis 126. A raw signal value 132 is illustrated, along with an oxygensensor value 128. The raw signal value 132 suffers a drop at or near thesame time as the oxygen sensor value 128, indicating a compressionfault. Thus, detecting a blocked signal on both sensors leads to agreater likelihood the fault is caused by compression.

Referring back to FIG. 6, as another example of the use of other signals74, the signal from a reference electrode may be employed in the faultdiscrimination method. For example, if the reference electrode signaldrifts or shifts, such may be an indication that the reference analyteis depleted. In these cases, the value measured by the referenceelectrode becomes particularly oxygen sensitive. Thus, when thereference electrode value drifts and/or becomes highly oxygen sensitive,a fault of depletion of the reference analyte may be discriminated. Anexample is shown by the graph 134 of FIG. 8B, in which the ordinaterepresents the reference electrode signal, the abscissa is time, and thecurve 138 illustrates a gradual drift downward of the reference signalelectrode potential. In such cases, responsive processing may includethe running of a potential sweep in order to detect the shift in thereference bias. Such potential sweeps may be part of a self diagnosticssuite of routines, and are described in greater detail below.

As yet another example of the use of other signals 74, where animplantable pump for a medicament is employed, data may be obtained fromthe pump insertion set, including data about pressure. Such may beadvantageously employed in fault discrimination. In this regard it isnoted that where pumps are employed, scar tissue may grow and suchimpedes delivery of a medicament. Using fast sampling or other suchquantification of the pressure required to move, or initiate themovement, of the stepper motor inside of a pump, a profile may be builtup of the required pressure versus the amount of scar tissue, and theprofile may be personalized to the user. In this way, a fault profilemay be developed of scar tissue buildup, and the same used as a signalcriterion for fault discrimination, as an additional signal, like thatof temperature. In other words, a signal characteristic or template maybe determined of scar buildup, and when the same is seen in an evaluatedsignal, the fault of scar tissue is discriminated. Once the fault isdiscriminated, the same may be used to adjust delivery and/or bolusdelivery and applied to future deliveries. Moreover, the same may beused to anticipate blockage.

As yet another example of the use of other signals 74, a signalpertaining to an impedance measurement may be employed between thesignal or working electrode (e.g., in a host) and an external electrode(e.g., on the skin), which may or may not be the same as a referenceelectrode. In this way, electrochemical impedance may be measuredbetween the physiological environment and the signal electrode. Evenmore importantly, changes such as increases or decreases of suchelectrochemical impedance may be employed in fault discrimination.Additional details of such impedance measurements are described below.

Next, various categories 76 of techniques will be seen, as well as a set78 of various techniques themselves. According to implementation, aparticular technique or a group of techniques may be employed from thecategories 76 or from the set 78. In most of these techniques, a step isgenerally included of detecting if the signal (or signal transform)deviates from what is expected or predicted, taking account of thenormal variance in the signal, by more than a predetermined amount, andmore particularly where such deviation is determined with apredetermined confidence level. Aspects of the normal variance in thesignal, and confidence levels thereof, and their calculation aredescribed in U.S. Patent Publication No. US-2009-0192366-A1 and U.S.Patent Publication No. US-2014-0278189-A1, both of which are assigned tothe assignee of the present application and herein incorporated byreference in their entireties.

The categories 76 include time-based techniques 82, frequency-basedtechniques 84, and time—frequency (“wavelet”) based techniques 86.Time-based techniques 82 are in many cases considered to be fastest. Itwill be understood that analyses may be performed using more than onetechnique category. Various types of techniques are now described.

For example, a step of raw signal analysis 88 may be performed, and thesame may be performed in the time domain or in the frequency domain.This step may be considered generally a precursor to or is generic toother steps performed. For example, such raw signal analysis 88 mayinclude an analysis of the frequency of noise, as certain faults lead tocertain respective prevalent noise frequency values, which can then beused in their discrimination. In the same way, noise may be divided intobinary states, such as high amplitude/low amplitude, highfrequency/low-frequency, and such binary states may be employed in faultdiscrimination. The smoothness of the data, or lack thereof, may beemployed in fault discrimination using raw signal analysis. For example,lack of smoothness may indicate the presence of a fault, and vice versa.Referring to the graph 142 of FIG. 8C, a raw signal value 144 isillustrated with a noise section 146. All other factors being equal, itis more likely that a fault has occurred in the noise section 146 thanin the remainder of the curve. This same determination would arise fromfrequency analysis.

Changes in the signal that are not related to physiology may be detectedby raw signal analysis. For example, maxima and minima exist forphysiological rates of change of glucose, and if rates of change aremeasured that are greater than the maxima, or less than the minima, suchmay indicate a fault. For example, referring to the graph 148 of FIG.8D, a raw signal value 152 is illustrated with a sudden decrease 154.The sudden decrease 154 may be of greater magnitude than would possiblyor ordinarily be encountered in a physiological system, e.g., a rawsignal value in a user would not be expected to exhibit such a drop (orconversely, a rise above normal physiological thresholds). Physiologicalcriteria may be determined based on a priori date from a particularpatient or sets or patients, and may be further individualized to aperson's normal glucose profile, for example. Accordingly,non-physiological apparent glucose changes may be discriminated as afault.

The direction of a signal artifact may also be taken into account aspart of the raw signal analysis. For example, and as described ingreater detail below, if an analyte concentration has a steep downwardtrend with noise, such may be associated with the faults of compressionor “dip-and-recover”. An example is shown in FIG. 8D at the portion ofthe curve indicated by section 154. Similarly, if the raw signal has asteep upward trend with noise, such may be associated with the fault ofan electrical short-circuit, e.g., from water ingress into thetransmitter contact area.

Referring back to FIG. 6, other signal processing related to raw signalanalysis 88 will also be understood, including those involving complexfrequency-based analysis, e.g., high pass filters, low pass filters, andmatch filters.

Similarly, a step of residual signal analysis 92 may be performed, inwhich raw signal data is analyzed vis-à-vis filtered signal data. Inmore detail, in yet another method for fault discrimination involvingexamination or evaluation of the signal information content, filtered(e.g., smoothed) data is compared to raw data (e.g., in sensorelectronics or in receiver electronics). In one such embodiment, asignal “residual” is calculated as the difference between the filtereddata and the raw data. For example, at one time point (or one timeperiod that is represented by a single raw value and single filteredvalue), the filtered data can be measured at 50,000 counts and the rawdata can be measured at 55,500 counts, which would result in a signalresidual of 5,500 counts. In some embodiments, a threshold can be set(e.g., 5000 counts) that represents a first level of noise (e.g., signalartifact) in the data signal when the residual exceeds that level.Similarly, a second threshold can be set (e.g., 8,000 counts) thatrepresents a second level of noise in the data signal. Additionalthresholds and/or noise classifications can be defined as is appreciatedby one skilled in the art. Consequently, signal filtering, processing,and/or displaying decisions can be executed based on these conditions(e.g., the predetermined levels of noise).

Although the above-described example illustrates one method ofdetermining a level of noise, or signal artifact(s), based on acomparison of raw vs. filtered data for a time point (or single valuesrepresentative of a time period), a variety of alternative methods arecontemplated. In an alternative exemplary embodiment for determiningnoise, signal artifacts are evaluated for noise episodes lasting acertain period of time. For example, the processor (in the sensor orreceiver) can be configured to look for a certain number of signalresiduals above a predetermined threshold (representing noise timepoints or noisy time periods) for a predetermined period of time (e.g.,a few minutes to a few hours or more).

In one exemplary embodiment, a processor is configured to determine asignal residual by subtracting the filtered signal from the raw signalfor a predetermined time period. The filtered signal can be filtered byany known smoothing algorithm such as those described herein, e.g., a3-point moving average-type filter. The raw signal can include anaverage value, e.g., where the value is integrated over a predeterminedtime period (such as over 5 minutes). Furthermore, it is noted that thepredetermined time period can be a time point or representative data fora time period (e.g., 5 minutes). In some embodiments, where a noiseepisode for a predetermined time period is being evaluated, adifferential can be obtained by comparing a signal residual with aprevious signal residual (e.g., a residual at time (t)=0 as compared toa residual at (t)=5 minutes.) Similar to the thresholds described abovewith regard to the signal residual, one or more thresholds can be setfor the differentials, whereby one or more differentials above one ofthe predetermined differential thresholds define a particular noiselevel. It has been shown in certain circumstances that a differentialmeasurement, as compared to a residual measurement as described herein,amplifies noise and therefore may be more sensitive to noise episodes,without increasing false positives due to fast, but physiological, ratesof change. Accordingly, a noise episode, or noise episode level, can bedefined by one or more points (e.g., residuals or differentials) above apredetermined threshold, and in some embodiments, for a predeterminedperiod of time. Similarly, a noise level determination can be reduced oraltered when a different (e.g., reduced) number of points above thepredetermined threshold are calculated in a predetermined period oftime.

In some embodiments, one or more signal residuals are obtained bycomparing received data with filtered data, whereby a signal artifactcan be determined. In some embodiments, a signal artifact event isdetermined to have occurred if the residual is greater than a threshold.In some exemplary embodiments, another signal artifact event isdetermined to have occurred if the residual is greater than a secondthreshold. In some exemplary embodiments, a signal artifact event isdetermined to have occurred if the residual is greater than a thresholdfor a period of time or amount of data. In some exemplary embodiments, asignal artifact event is determined to have occurred if a predeterminednumber of signal residuals above a predetermined threshold occur withina predetermined time period (or amount of data). In some exemplaryembodiments, an average of a plurality of residuals is evaluated over aperiod of time or amount of data to determine whether a signal artifacthas occurred. The use of residuals for noise detection can be preferredin circumstances where data gaps (non-continuous) data exists.

In some exemplary embodiments, a differential, also referred to as aderivative of the residual, is determined by comparing a first residual(e.g., at a first time point) and a second residual (e.g., at a secondtime point), where a signal artifact event is determined to haveoccurred when the differential is above a predetermined threshold. Insome exemplary embodiments, a signal artifact event is determined tohave occurred if the differential is greater than a threshold for aperiod of time (or amount of data). In some exemplary embodiments, anaverage of a plurality of differentials is calculated over a period oftime or amount of data to determine whether a signal artifact hasoccurred. Other details of residual analysis are described in U.S. Pat.No. 8,260,393, incorporated by reference above.

Returning again to FIG. 6, pattern analysis 94 may also be performedwhich may lead to certain expected or predicted changes in signalvalues, measured in an absence of faults, and thus if a signal change ismeasured that fits the pattern, a fault need not be discriminated.Without pattern analysis, a similar change in signal value may well leadto a fault being erroneously discriminated. Conversely, if a signal isreceived that does not fit the pattern, a fault may be detected and,depending on the signal characteristics and/or clinical context, a faultmay be discriminated. Thus, pattern analysis can assist in thediscrimination of faults.

In more detail, certain signal characteristics or patterns may indicateor be signatures for various faults, and when such signalcharacteristics or patterns are seen in subsequent signals, such mayprovide evidence that the respective fault is recurring. An example isprovided below of the use of signal templates. A template is determinedfor a given fault, and a signal is projected onto the template todetermine how much of the signal can be attributed to the templatewaveform, and thus to the fault associated with the template waveform.Such is described in greater detail below.

Additional details of such pattern analysis techniques are provided inU.S. Patent Publication No. US-2013-0035575-A1 and U.S. PatentPublication No. US-2014-0129151-A1, both of which are assigned to theassignee of the present application and herein incorporated by referencein their entireties.

Another step which may be performed for signal discrimination is that of“slow versus fast” sampling (step 96). In these techniques, data issampled at two or more different sampling rates, simultaneously orsequentially. Such techniques may be performed constantly or only atcertain times, e.g., during a “self-diagnostic” mode. For example, datamay be sampled both at 30 second intervals and at five-minute intervals.Data sampled at 30 second intervals is more granular and can showfeatures related to noise components and faults which are not apparentfrom the data sampled at five-minute intervals, especiallyhigh-frequency noise components.

For example, referring to FIG. 9A, data sampled at 30 second intervalsis illustrated by the solid line 162, and data sampled at five-minuteintervals is illustrated by the dotted line 164. Along the line 162,that time point 166 a sudden drop is seen, with a corresponding suddenrise at time point 168. This drop and rise is characteristic of thefault of “compression”, e.g., where a user's weight, or a portionthereof, has impinged on their sensor and associated electronics (thedrop), and then subsequently removed the impingement (the rise). FIG. 9Billustrates another example of the use of slow versus fast sampling,where not only can fast sampling provide better curve definition forfault discrimination, but additional features can also be gleaned fromthe data. For example, the data sampled every 5 minutes is sufficient toknow the glucose concentration, and to indicate certain spikes likelydue to noise. However, examination of the same data sampled every 30seconds clearly indicates the presence of high-frequency noise portions167. Thus, using both slow and fast sampling provides for better noisediscrimination as well as a reduction in the time lag before noise isnoticed and responsive processing occurs. The analysis of suchhigh-frequency noise components using fast sampling further allows foran accurate end-of-life detection method, extending wear duration andmaking more efficient replacement claim procedures. Another example ofend-of-life detection is given below.

As another example of signal processing, a step of employing fuzzy logic103 may be used. Such can conceptually be applied to any noise detectionscheme, where the noise detection measures the level of noise, ratherthan a binary or broadly categorized noise level scheme. In particular,using fuzzy filtering, filtering may be applied more incrementally orsmoothly, by adaptively weighting the raw versus filtered signal toachieve an incrementally more or less aggressively filtered signal.Fuzzy filtering may also be applied to the slow versus fast samplingsignals techniques, or indeed with any techniques employing twodifferent resolutions of signal. The fuzziness of the filter may beapplied based on the level of noise and/or clinical context.

In more detail, and as noted above, residual analysis can be employed innoise management algorithms, including residuals (differences) betweenraw and unfiltered values or delta residuals, i.e., the change from oneresidual to another. These algorithms are useful in estimating noiselevels. In one implementation, the residual may be passed through threedifferent filters, e.g., one slow-moving, one medium moving, and onefast-moving, and based on the ratio of the outputs of the threedifferent filters to a very slow moving average, the algorithm candetermine whether the noise state is clean, light, medium, or severe.

One problem with such techniques is that they are binary. In one casethe signal is “clean” and the delay or time lag in the signal is justrelated to the sampling periodicity, e.g., e.g., 5 minutes. In anothercase, filtering is applied, and the time lag is related to the samplingwindow of the filter, e.g., 10 minutes For noisy signals, this long timelag can be problematic, particularly if the user's glucose level isdropping fast, e.g., −5 mg/dL/min. Use of fuzzy logic and in particulara fuzzy filter can reduce this delay as follows.

In particular, an estimated glucose value can be determined by theequation:

EGV=(Count−Baseline)/Slope

where count=2*α*Filter(N)+(1−α)*Raw(N)where Filter(N) represents the filtered signal and Raw(N) represents theraw signal. α is a weighting factor that is close to zero when theresidual or delta residual is small, and close to one when theresidual/delta residual is large. α may be described by any of a varietyof continuous functions, but in many cases is linear and monotonicallyincreasing.

The calculation of a may vary based on the underlying model used. Atevery point, the absolute residual/delta residual may be calculated, soa new weight may be calculated at every point. Besides absoluteresiduals, other metrics may be utilized, e.g., lightly filteredresiduals, medium filtered residuals, severe filtered residuals, ratioof lightly-filtered residual to slow-moving filtered residual, ratio ofmedium-filtered residual to slow-moving filtered residual, ratio ofsevere-filtered residual to slow-moving filtered residual, and so on.Signed residuals (negative/positive) may be utilized to manipulate thetime lag, e.g., sensor lags on glucose rises, and sensor leads onglucose drops. For example, if the underlying trend is a drop, and thesensor is leading, then additional filtering can be afforded. On theother hand, if the trend is a rise, then the raw signal may be averaged,provided the current residual is small, and a projected value could becalculated for 5 minutes from the current time, and additional weightgiven to the projected value over the raw value. In this way, the fuzzyfilter may be applied incrementally. In this way, if there is verylittle noise, filtering may occur but only lightly and not aggressively.If significant noise is present, filtering may be applied moreaggressively.

In an even more sophisticated implementation, the concept of a fuzzyunit (FU) may be defined as shown below:

${{Fuzzy}\mspace{14mu} {Unit}\mspace{14mu} ({FU})} = {100*\frac{\begin{matrix}{{Medium}\mspace{14mu} {Filtered}\mspace{14mu} {Residual}} \\\left( {{or}\mspace{14mu} {DeltaRresidual}\mspace{14mu} {if}\mspace{14mu} {one}\mspace{14mu} {can}\mspace{14mu} {be}\mspace{14mu} {calculated}} \right)\end{matrix}}{{Slow} - {{Moving}\mspace{14mu} {Average}}}}$

When the first fuzzy unit is calculated, the filter may be initializedas follows:

CurrentNoisePercent=FU;

PreviousNoisePercent=previous prediction of the FU;RawError[n]=the error between the CurrentNoisePercent and thePreviousNoisePercent;SmoothedError[n]=the filtered error between the CurrentNoisePercent andthe PreviousNoisePercent, e.g., 0;α=a smoothing factor between PreviousNoisePercent and theCurrentNoisePercent, e.g., 0.65;β=a smoothing factor between the smoothed error and the raw error, e.g.,0.65; and

${NoiseWeight} = {{\frac{1}{2}\left\lbrack {1 + {{erf}\left( \frac{{CurrentNoisePercent} - \mu}{\sqrt{2\sigma^{2}}} \right)}} \right\rbrack}.}$

NoiseWeight is employed to create a new filtered count as shown below:

${{FilterCount}^{\prime}\lbrack n\rbrack} = {{{NoiseWeight}*{{FilterCount}\lbrack n\rbrack}} + \frac{\left( {1 - {NoiseWeight}} \right)*{{RawCount}\lbrack n\rbrack}}{2}}$

The relationship between the fuzzy unit FU and NoiseWeight takes theshape illustrated in FIG. 10A. As may be seen in the figure, as noiseincreases, the filter is applied to an increasing extent.

Referring to the flowchart 75 of FIG. 10B, after the first fuzzy unit iscalculated, the following steps may be executed for each subsequentcalculation of the fuzzy unit (CurrentNoisePercent) (step 77).

A first step to calculate RawError and to store the same (step 79):

${{RawError}\lbrack n\rbrack} = {{\frac{{PreviousNoisePercent} - {CurrentNoisePercent}}{CurrentNoisePercent}}.}$

If n>=3, β is updated (step 81) as shown below:

${{TwoPointError} = {{{{RawError}\left\lbrack {n - 2} \right\rbrack} - {{RawError}\left\lbrack {n - 1} \right\rbrack}}}},{{OnePointError} = {{{{RawError}\left\lbrack {n - 1} \right\rbrack} - {{RawError}\lbrack n\rbrack}}}},{{DeltaError} - {\frac{{TwoPointError} - {OnePointError}}{OnePointError}}},$

and subsequently:

$\beta = {{\frac{1}{2}\left\lbrack {1 + {{erf}\left( \frac{{DeltaError} - \mu}{\sqrt{2\sigma^{2\;}}} \right)}} \right\rbrack}.}$

And where, for example, μ=0.75 and σ=0.29, β takes the shape indicatedin FIG. 10C, which indicates that as the change in the error increases,α increases and thus more emphasis will be placed on the currentSmoothedError.

A next step is to update the SmoothedError (step 83):

SmoothedError[n]=(1−β)*RawError[n]+β*SmoothedError[n−1].

A next step is to update α (step 85):

$\alpha = {{\frac{1}{2}\left\lbrack {1 + {{erf}\left( \frac{{SmoothedError} - \mu}{\sqrt{2\sigma^{2\;}}} \right)}} \right\rbrack}.}$

And α takes the shape illustrated in FIG. 10D.

A next step is to make a forecast of the CurrentNoisePercent (step 87):

PreviousNoisePercent=α*CurrentNoisePercent+(1−α)*PreviousNoicePercent.

This step is followed by updating the NoiseWeight (step 89):

${NoiseWeight} = {\frac{1}{2}\left\lbrack {1 + {{erf}\left( \frac{{PreviousNoisePercent} - \mu}{\sqrt{2\sigma^{2}}} \right)}} \right\rbrack}$

The new FilterCount is then calculated (step 91):

${{FilterCount}^{\prime}\lbrack n\rbrack} = {{{NoiseWeight}*{{FilterCount}\lbrack n\rbrack}} + \frac{\left( {1 - {NoiseWeight}} \right)*{{RawCount}\lbrack n\rbrack}}{2}}$

The FilterCount′ and RawCount are then passed into an appropriate noisemanagement algorithm (step 93 (FIG. 10B)), and then the point and noisestates are updated, e.g., using probabilistic thresholds. Exemplaryprobabilistic thresholds are shown in the table below:

If NoiseWeight > 0.95 PointNoise = severe NoiseState = severe ElseIfNoiseWeight > 0.82 PointNoise = medium NoiseState = medium ElseIfNoiseWeight > 0.4 PointNoise = light NoiseState = light Else PointNoise= clean NoiseState = clean

It will be understood that other thresholds may also be employed.

In tests, fuzzy filters have provided significantly faster responses tonoise spikes as well as more rapid recovery from noise episodes thanillustrated by prior efforts simply involving filtering. Fuzzy filtershave also exhibited higher accuracy than such prior efforts.

In yet another variation in signal analysis methods, metrics may haveweights associated, and the weights may be standard or may varydepending on metric. In this variation, accommodation is made for theobservation that some metrics are larger indicators of a particularfault than others. For example, skewness and variance are largerindicators for oxygen noise (indicated by high-frequency noise and adownward trend) than they are for a shower spike (indicated by a smoothupward rise).

Other types of signal processing will also be understood from thisdisclosure to be employable according to implementation, and otherfactors, parameters, and variables may be used in the faultdiscrimination. For example, timestamps of data may be used in certainanalyses, e.g., to detect certain time-based patterns or to determinetime since implantation, which bears strongly on the determination ofend-of-life. In this respect it is noted that in some cases the rawsignal data correlates to established patterns of the patient. Forexample, raw sensor data indicating a potentially faulty situationbecause of an abnormally high signal value may at first appear toindicate a fault, but may also be caused by the user eating a regularmeal. The determination that the user has eaten a regular meal may be byway of timestamp data, as well as machine learning (or other technique)in which a pattern may be established. Similarly, a spike in the data ata consistent time of day may be indicative of a water related error,such as related to a daily shower. Similarly, other types of faults maybe more likely to occur at night, such as compression artifacts.

Other types of signal processing may include analysis of a time durationsince the implant of the analyte monitor, e.g., which may beparticularly important to examine to account for faults or errors thatmay occur over time or to older implants.

Finally, it is noted that where a specific factor, parameter, orvariable has been noted above, a corresponding duration over which thesame has occupied a range of values may be employed in faultdiscrimination, where the range of values is a narrow range or a widerange. Combinations of the above factors, parameters, and variables, mayalso be employed.

Clinical Context Information

Types of data corresponding to clinical context information are nowdescribed. These types of data relate to the observation and treatmentof actual patients rather than simply looking at internal signalsunknown to the patient. However, it should be understood that clinicalcontext information may be derived from internal signals, usingprocessing that transforms the internal signals into data related to theobservation and treatment of actual patients. For example, while the rawsensor signal is unknown to the patient, the actual glucoseconcentration, calibrated and transformed from the raw signal,constitutes clinical context information 186. Similarly, whiletemperature and time information may be considered internal information,the comparison of temperature and time information to certain clinicalcontext criteria (e.g., sleep/awake, showering, sedentary/activeinformation) may be used to derive clinical context information, Ingeneral such clinical context information includes anything that affectsthe person with the condition, e.g., diabetes, including social,emotional, physical, and environmental influences, and indeed anythingwhich may relate to or impacts the physiological health or environmentsurrounding the patient. By identifying the clinical context, additionalintelligence is gained for fault discrimination and responsiveprocessing purposes.

FIG. 11 illustrates various types of data or other information that mayconstitute or be involved in the determination of clinical contextinformation 186. A key contributor to clinical context information 186is the glucose concentration data 184. This data may include aspects 188such as the actual clinical value, its rate of change, acceleration,higher order derivatives, and the like. The glucose concentration data184 may also include aspects 192 such as ranges of glucoseconcentrations, e.g., ranges maintained by the patient's glucoseconcentration, as well as durations over which users have clinicalglucose values within specific ranges. Similarly, states may be definedand used as ranges, e.g., hypoglycemic, hyperglycemic, or euglycemic.Such a state data may also include impending, predicted, or expectedstates. Other potential contributors to glucose concentration data 184may include whether the patient is in a steady-state or is experiencingchange in their glucose concentration.

Analyte concentration such as glucose concentration, when used asclinical context information, constitutes information that has beentranslated from a raw signal into a meaningful value for diabetesmanagement, e.g., mg/dL or mmol/L, or time derivatives includingmg/dL/min or mg/dL/min². Such is different from “sensor data” because ithas been calibrated for clinical relevance. Quantities derived in partfrom glucose concentration information may also be employed, includingglycemic urgency index (“GUI”), dynamic risk (“DR”), static risk (“SR”),and the like.

In many implementations, clinical context information will include, orbe determined from, at least some aspects of analyte concentration,e.g., glucose concentration, or from the quantities derived in part fromanalyte concentration as noted above, e.g., glucose rate of change,glycemic state, GUI, and the like. In other words, where clinicalcontext information is employed in fault discrimination and responsiveprocessing, the clinical glucose value or a state pertaining theretowill be used. For example, given a particular fault, responsiveprocessing may often depends on whether the user is hypoglycemic,hyperglycemic, or euglycemic. Such states may bear on whether a glucosedisplay is suspended and/or whether a warning is given to the user. Inthe same way, the rate of change may often be employed, because if afault causes a user's glucose value to become unknown or uncertain, theresponsive processing will strongly bear on whether the glucose levelwas rising or falling prior to the fault, as well as the speed of riseor fall. Higher order derivatives may be employed to determine if auser's glucose level is likely to return to normalcy or if furtherexcursions are expected. Thus, the clinical glucose value and relatedparameters are often used in fault discrimination and responsiveprocessing.

Regarding non-glucose concentration related information, the same mayinclude information and data relating to age 194, as such data often hasa strong bearing on the clinical context; in other words, whether or nota fault is discriminated, or the type of fault, may depend on the age ofthe patient. Put another way, sensor data may be regarded as faulty forone patient but not for another, and age can be an indicator of “whichbucket the data falls into”. For example, for very young patients aswell as elderly ones, each data point may be given significant weight asthe consequences of faulty data may be more dire than that for strongeryoung adult patients. Accordingly, the system may be configured to beespecially sensitive and to thus discriminate more faults in suchsituations and for such patients. It will be understood that generallyage is one of many clinical context data variables that may be takeninto account in the determination of the clinical context information186, and thus the actual resulting fault discrimination and responsiveprocessing behavior will depend on many factors.

Similarly, anthropometric data 196, which generally relates to bodyinformation such as BMI, can also bear on the determination of whether afault has occurred. One way of measuring anthropometric information forsuch uses is by measuring the impedance from the tip of the sensor tothe base patch, as discussed in greater detail above and below. Whilethe above discussion was related to measuring the impedance in order todetermine an internal aspect of the sensor or sensor electronics, hereit is noted that impedance measurements may be employed to determine anexternal aspect, and in particular clinical context information.Impedance measurements can result in determinations of clinical contextinformation including tissue type, BMI, and the like.

A further aspect includes data 185 about whether drugs have beenadministered such as insulin. In this case, raw sensor data indicating apotentially faulty situation because of an abnormally low signal valuemay indicate a fault, but may also be caused by a recent injection orbolus of a medicament such as insulin. By consideration of such clinicalcontext, that which may otherwise be ascribed to a fault may bedetermined to be actual physiological data, i.e., not a fault.Conversely, if a recent injection or bolus has been made, but the signalis abnormally high, such may increase the likelihood of a fault beingdiscriminated. Data about potentially interfering drugs may also beconsidered in the fault discrimination.

Yet another type of clinical context information includes data 187 aboutthe external temperature as compared to clinical context criteria todetermine clinical context information. Generally the temperature dataand its comparison with criteria is combined with other clinical contextinformation in the evaluation of a particular patient situation. Suchclinical context information may indicate that the patient has entered ahot tub, shower, has been working out, has a fever, or the like.

Yet another aspect includes data 191 about the activity level of thepatient, as well as data 193 about exercise relating to the user. Data191 or 193 may be inferred from another wearable sensor, as well as a“fitband”, gyroscope, accelerator in on-skin electronics, anaccelerometer or GPS in a smart phone or smart watch, or via patientinput, as well as other means. The data 191 may be quantitative orqualitative, and in the latter case may be measured as, e.g.,“sedentary” or “active”. Other gradations will also be understood. Thedata 193 may also be quantitative or qualitative, and in the formercase, may provide an indication of the amount of movement the sensor hasundergone, the period of time over which the movement has occurred, andderived quantities such as calories burned.

Yet another contributor to clinical context information 186 may be data189 about the fault history of the patient. In particular, certainpatients may have a particularly active fault discrimination history.Such patients include those with high wound responses, or who more oftensee early wound effects, or the like, which increase the overalllikelihood of such a fault being seen for that patient in futuresessions. Other patients may be more prone to compression faults, andthis tendency may be factored into the analysis.

A further contributor to clinical context information 186 is data 195about the clinical use of the data. This contributor pertains to how thedata is used, e.g., whether in a closed loop system, open loop system,artificial pancreas system, with an integrated pump, or the like. Inmore detail, if the data is used in a closed loop system, the same mayprovide a driving factor for a pump which administers a medicament,e.g., insulin. In a closed loop system, the determination of whether agiven signal is faulty may, for example, be more conservative becausemedicament delivery depends on the signal. In other words, the systemmay be configured to discriminate more or have a higher sensitivity forfaults in this clinical context. Conversely, in an alternativeimplementation, where a pump driving algorithm has its own faultdiscrimination routines, the system may be configured to discriminateless or have a lower sensitivity for faults.

The above is premised on a potentially faulty signal driving a pump.Pump information may also be employed in a converse fashion tosupplement, inform, and drive fault detection. For example, if a largebolus of insulin was recently injected, then a negative rate of changein glucose would be expected, but not a positive spike in the signal.Accordingly, if a positive spike in the signal occurs, such is morelikely to be a fault that an actual glucose excursion. Variations of theuse of “clinical use” data will also be seen given this teaching.

Another contributor to the clinical context information 186 is data 197about patient interaction with their analyte monitor, e.g., CGM. Thelevel to which a patient or user is interactive with their analytemonitor may be a factor in the determination of the clinical contextinformation. For example, if a user does not consult their CGM verymuch, i.e., is noninteractive, then it may be presumed that eachinteraction, i.e., each data point received by the user, bearssignificant weight in user management of their disease, just based onthe relative rarity of data points the user encounters. Conversely, forhighly interactive users, each data point is important, but a fault maybe less dangerous because the user is likely to receive another datapoint relatively soon. Patient interactions with their CGM can betracked by button presses on the receiver, menu selections or screensviewed, calibrations, or the like.

Other clinical context information will also be understood. For example,correlation with normal glucose behavior may constitute clinical contextinformation. In this example, patterns of glucose values may beestablished for a patient. Such patterns may be time-based orevent-based, but generally indicate normal glucose behavior for apatient. Time-based patterns may be based on time of day, a weeklybasis, a monthly basis, and so on. A current glucose levels can then becompared to normal or expected glucose patterns and profiles for thesame time of day, week, or month, respectively deviations from the normmay then indicate a clinical event. Wavelet correlations may be employedin this analysis.

A local pressure surrounding the sensor may be employed in thedetermination of clinical context information, as the same can detectcertain movements (or lack thereof) of the patient that may affectsensor function. Appropriate pressure sensors may be incorporated on oradjacent the sensor and/or sensor electronics described above byincluding a strain gauge or a piezoelectric material on the shell orouter body of the transmitter body, or pressure plates, gauges, ormaterials in the base (e.g., flexible portion) of the body. Suchthin-film sensors may be employed for pressure detection andquantification. Generally, however, the use of such data is as an inputto the overall determination of clinical context, and not merely todetermine sensor function itself. In one implementation, the pressuremay be employed as an input in the determination as to whether thepatient was moving, sedentary, awake, asleep, and so on. For example, asudden increase in pressure as detected by such a sensor may be combinedwith pattern data and/or time of day data (e.g., a patient usually goesto sleep at the same time the pressure increase occurred), and thepatient movement data (e.g., the patient shows little to no movement).These signals evaluated together may lead to a clinical context ofmoving, sedentary, awake, asleep, or the like being determined.Additional details of certain of these aspects are provided in US PGP2012/0078071, owned by the assignee of the present application andherein incorporated by reference in its entirety. Moreover, exemplarythin-film sensors are described below which may be integrated into thesensor electronics or the transmitter housing.

Certain types of clinical context information discussed above may beprovided by the patient and entered in the monitor, particularly if themonitor is embodied by a smart phone or other device with a substantialuser interface. For example, a user may be queried as to meals ingested,exercise performed, and the like. In some cases, a user query may beprompted by a fault, so as to disambiguate the same. For example, a usercould be queried as to whether they were laying on top of their sensor,e.g., to discriminate a compression fault. Other questions will also beunderstood.

A patient query may be prompted to determine if a fault was preceded bya meal, so as to attempt to resolve an ambiguous rise in signal value.For example, if the query determines that the patient recently ingesteda meal, a rise in signal value will likely be attributable to apost-prandial rise rather than an error or fault. Such information mayalso be provided by a processor module, e.g., in data communication witha food ingestion application, a camera for imaging a meal, and the like.

Similarly, a patient query may be prompted to determine if a fault waspreceded by an insulin intake. Insulin information may also be providedby an integrated pump. For example, a sudden decrease in raw signal maybe determined in this way to be the effect of a bolus of insulin ratherthan a fault.

Yet another type of clinical context information includes behavioral orcontextual information. Such information may correspond to how a patientuses their mobile device, and thus gives context to certain datadetermined by the device. Behavioral or contextual information may beobtained via the system and can include an amount of interaction,glucose alerts/alarms states, sensor data, number of screen hits, alarmanalysis, events (e.g., characteristics associated with the user'sresponse, time to response, glycemic control associated with theresponse, user feedback associated with the alarm, not acknowledgingalerts/alarms within X minutes, time to acknowledgment of alerts/alarms,time of alert state, and so on), diabetes management data (e.g., CGMdata, insulin pump data insulin sensitivity, patterns, activity data,caloric data), data about fatty acids, heart rate during exercise,IgG-anti gliadin, stress levels (sweat/perspiration) from a skin patchsensor, free amino acids, troponin, ketones, adipanectin, perspiration,body temperature, and the like. The inputs may be provided by a sensorin data communication with the monitoring device. In someimplementations, the information may be obtained through an intermediarysuch as a remote data storage. In some situations, a patient may usemore than one device to track their diabetes (e.g., glucose displayed onmedical device receiver and smart phone).

Contextual information which may be provided as clinical contextinformation includes a person's biology, location, sensing surroundings(e.g., light, sound level), environmental data (e.g., weather,temperature, humidity, barometric pressure). The inputs may be receivedvia a peer-to-peer or a mesh network via machine-to-machinecommunication. Context information can include daily routine information(which may change especially from weekdays to weekends) from acalendaring application. Context information can include a frequency oftouching or grabbing the monitoring device, even if not interacted with,based on a sensed motion of the device.

Photos can provide contextual information. For example, photos of one ormore of: a glucose meter reading, an insulin pen or pump JOB, a location(e.g., a gym, park, house, Italian restaurant), or a meal may be used toprovide context information. The photos may be processed to identify,for example, caloric intake for the meal shown in the photo. The type ofinsulin used may also be provided to the monitoring system as a usefulcontribution to the clinical context information. Context may also beprovided by basal or bolus settings provided to or determined by themonitoring device.

Other inputs to the clinical context information which constitutecontext/behavioral data may include data types referenced elsewhere innon-context/behavioral inputs, such as exercise information from afitness bike or the like, glucose sensor information from a bloodglucose (BG) meter or CGM, insulin delivery amounts from insulindelivery devices, insulin on board calculations for the device, andother device provided or calculated information. Othercontext/behavioral data inputs to the GUI determination may include:hydration level, heart rate, target heart rate, internal temperature,outside temperature, outside humidity, analytes in the body, hydrationinputs, power output (cycling), perspiration rate, cadence, andadrenaline level, stress, sickness/illness, metabolic/caloric burn rate,fat breakdown rate, current weight, BMI, desired weight, target caloriesper day (consumed), target calories per day (expanded), location,favorite foods, and level of exertion.

For any of the above referenced behavior or contextual inputs, thesystem may be configured to receive and/or generate analytical metricsbased on the inputs. For example, a composite value may be generatedbased on the glucose level, temperature, and time of data generatedindex value for the user. The composite value may then be considered inthe determination of the contribution to the clinical contextinformation from the behavior and contextual information.

This information can be collected from various sensors within or outsideof the device, such as an accelerometer, GPS, camera data, and the like,as well as third-party tracking applications, including sleep cycleapplications. For example, such tracking applications may employgeolocation to determine context and behavior. Moreover, context andbehavior may also be determined by use of social networking informationavailable about the user, where a social networking feed, associatedwith the user, is arranged to provide a source of data in forming theclinical context information.

Additional details about context and behavior information may be foundin U.S. Patent Publication No. US-2015-0119655-A1, owned by the assigneeof the present application and herein incorporated by reference in itsentirety, and in particular at FIG. 4 and accompanying text.

Signals and signal analysis, as well as clinical context information,are further discussed below in the context of the description ofspecific methods, as well as in several examples.

As noted in FIG. 5, clinical context information may be used both infault discrimination as well as in responsive processing. The followingfigures detail these methods. Referring first to FIG. 12 A, a flowchart222 illustrates a first regime (regime I) in which fault discriminationoccurs from signal analysis alone, without regard to clinical contextinformation. In this regime, a first step is to discriminate the faultfrom the signal alone (step 228). Clinical context information may thenbe received or otherwise determined (step 232). The discriminated faultis then responded to based on the context (step 234). In other words,there are two separate metrics, i.e., the signal data and the clinicalcontext, and the former is used as a single metric to discriminate thefault and the latter determines the responsive signal processing (giventhe particular discriminated fault).

The table of FIG. 12B illustrates regime I in another way. First, asignal behavior SBi leads to a corresponding discriminated fault DFi. Inthe same way, a context variable VCj leads to corresponding clinicalcontext data CDj. SBi and CDj are then used to determine a responsiveprocessing RPji.

For example, and referring to the graph 236 of FIG. 12C, in which asbefore the abscissa axis 126 represents time and the ordinate axis 136represents the raw signal, a steep downward trend 237 (SBi) is seen inthe raw signal 235, accompanied by noise, which then flattens out andhas less noise or variability 239 on the flattened portion. These signalcharacteristics may indicate by themselves a fault of compression (DFi).If one of the variables (VCj) known about the clinical context of theuser indicates that it is the usual time for the user to go to sleep(CDj), then the responsive processing (RPji) may be to do nothing. Onthe other hand, if one of the variables known about the clinical contextof the patient indicates that it is unlikely the user is sleeping (CDk),the responsive processing may be to perform self diagnostics (RPki) orto prompt the user to check their sensor.

As another example, the same detected fault may be handled differentlydepending on other aspects of the clinical context. For example, avariation in responsive processing may occur based on whether themeasured glucose level is high versus low, or whether the rate of changeof glucose level is slow versus fast.

Next, regime II is illustrated in FIG. 13. FIG. 13A shows a flowchart224 in which fault discrimination occurs from signal analysis incombination with clinical context information. In this regime, a firststep is to receive the signal from the analyte monitor, and optionallyperform any of the various signal processing functions described above(step 242). Prior to, subsequent to, or contemporaneous with thereception of the signal, clinical context information may be received ordetermined (step 244). The fault is then discriminated based on thesignal and the received clinical context data (step 246). In otherwords, two separate metrics are used to discriminate the fault, i.e.,signal data and clinical context, rather than just one as in regime Iabove. The fault is responded to appropriately, based on the faultitself (step 248).

The table of FIG. 13B illustrates regime II in another way. First, asignal behavior SBi is used in combination with clinical context dataCDj to lead to a corresponding discriminated fault DFji, which is afault discriminated not just on the basis of the signal data but also onthe basis of clinical context data. Responsive processing RPji is thendirectly based on the discriminated fault DFji.

For example, and referring to the graph 236 of FIG. 13C, a steep upwardtrend 238 in the raw signal (SBi) may potentially indicate a fault ofwater ingress, but the indication is ambiguous because other factorscould also cause such behavior. If one of the variables (VCj) knownabout the clinical context of the patient indicates that it is the usualtime for the user shower (CDj), then CDj may be used in combination withSBi to disambiguate the fault and discriminate a fault of water ingress(DFji). Then the responsive processing (RPji) may be to do nothing. Onthe other hand, if one of the variables known about the clinical contextof the patient indicates that it is unlikely the user is showering(CDk), then the fault DFki may be discriminated and the responsiveprocessing may be to perform a step of self diagnostics (RPki).

Finally, regime III is illustrated in FIG. 14. FIG. 14A shows aflowchart 226, in which fault discrimination occurs from signal analysisoptionally in combination with clinical context information, but whereclinical context information is also used to drive the responsiveprocessing. In this regime, a first step is to receive the signal fromthe analyte monitor, and optionally perform any of the various signalprocessing functions described above (step 252). Prior to, subsequentto, or contemporaneous with the reception of the signal, clinicalcontext information may be received or determined (step 254). The faultis then discriminated based on the signal and optionally also on thereceived clinical context data (step 256). The fault is responded toappropriately, based on both the fault and the clinical context (step258).

The table of FIG. 14B illustrates regime III in another way. First, asignal behavior SBi is used optionally in combination with clinicalcontext data CDj to lead to a corresponding discriminated fault DFji,which is a fault discriminated on the basis of the signal data andoptionally also on the basis of clinical context data. The discriminatedfault DFji is then used in combination with clinical context data CDk todetermine a step of responsive processing RP (k-ji).

The above regimes are exemplary, and it will be understood that otherregimes are also possible. For example, and referring to the flowchart261 of FIG. 15, in some cases it may not matter how the faultdiscrimination is characterized and/or discriminated, so long as boththe signal data (step 262) and the clinical context (step 264) are takeninto consideration when determining responsive processing (step 266).That is, the fault discrimination or categorization may not be requiredas a separate step.

In another variation, a “zone of indifference” may be defined for oneparameter, factor, or variable (collectively, “metrics”), e.g., clinicalglucose value, or for many or all of these, e.g., clinical glucosevalue, rate of change, smoothness of trace, etc. In such a zone ofindifference, faults may be prohibited or suppressed because the effector danger of a fault is defined to be low. Conversely, a “zone ofdanger” may also be defined in which faults are always discriminated andin which responsive processing always occurs.

In some cases, just a single input may be employed to determine clinicalcontext information, where the single input is compared against clinicalcontext criteria and the results of the comparison used to determine theclinical context information. The single input may be based on thesignal received from a sensor, e.g., a CGM sensor, or may be based on adifferent type of input, e.g., time of day. In other cases, multipleinputs may be employed to determine clinical context information aboutone or more faults, wherein one or all of the multiple inputs arecompared against clinical context criteria and/or otherwise combined bya mathematical formula.

In any of these regimes, the discriminated fault may be determined tofall into one of several predetermined fault categories, and theresponse to the fault may then be at least in part determined by thecategory the fault is in. Exemplary fault categorization schemes are nowdescribed.

Referring to the diagram 268 of FIG. 16, a fault categorization schemeillustrated. In this scheme, a categorization scheme 272 of faultdiscrimination may be broadly categorized into two types: those faults274 that are detectable and treatable without user intervention, andfaults 276 that are detectable but not treatable without userintervention, where user intervention corresponds to the user performingan act to correct the fault, e.g., “rolling over” if a compressionfault, providing information to confirm a fault type, e.g., answering aprompted question or providing a reference glucose value, or performingtreatment of their diabetes without the use of the CGM data, e.g.,treating diabetes based on their meter value. For faults 274, variousprocessing steps may be undertaken to provide service to the user untilsuch time as the fault is alleviated or otherwise responded to. Forexample, an estimated or predicted signal 276 may be provided to theuser. Alternatively, a processed signal 278 may be provided to the user,where the processing includes steps of filtering, smoothing, or othersteps as required to reduce the effect of the fault. For example, wherethe signal undergoes a rapid upswing, typical of a water ingress fault,the signal may be replaced with a short-term prediction. Alternatively,if random noise is encountered, the signal can be filtered or smoothed.

In the other categorization, faults 276 are detected but cannot be fullyresponded to by the system. In this case, a warning 282 may be providedto the user that the displayed clinical glucose value, or GUI, may beinaccurate or should not be relied upon. Two examples are given in FIG.16. First, a dip-and-recover fault 284 may be encountered, e.g.,corresponding to an early wound response. With such a fault, a user maybe warned that their glucose level may be incorrect. Another example isa compression fault 286. If this type of fault is detected, theresponsive processing may be to prompt the user to change position.

It is noted that the above relates to responsive processing or otheractions taken once a fault is discriminated. The act or step of faultdiscrimination itself entails steps of signal analysis and optionallyalso knowledge of clinical context. The responsive processing generallyfollows from the fault discrimination.

The diagram 290 of FIG. 17 illustrates yet another categorization scheme292 which may be employed in fault discrimination. In the categorizationscheme 292, faults are divided into transient faults 294 and permanentfaults 296. Transient faults 294 are those that tend to self—alleviateor self—cure, e.g., faults 298 related to compression, faults 302related to shower spikes, and faults 304 related to transient noise.Permanent faults 296 are those that are not cured or remedied over time,including oxygen noise 306 encountered at the end-of-life of the sensor.

The diagram 308 of FIG. 18 illustrates yet another categorization schemewhich may be employed in fault discrimination. In a categorizationscheme 312, exemplary fault categories are indicated, categorized by aspecific technical category. For example, faults are divided into faults314 relating to the local environment around the sensor causing anerroneous measurement, and faults 316 relating to system errors which inturn cause erroneous signal artifacts. The faults 314 tend to be morecompartmentalized and local. Examples of faults 314 include faults 318relating to compression and faults 322 relating to early woundresponses. An example of a fault 316 includes those relating to waterspikes, which in many cases are caused by seal failures.

In each of these cases, i.e., compression, early wound response, and awater spike or seal failure, as well as with other signal behaviors,there would exist predetermined signal criteria used by the faultdiscrimination and responsive processing routine or algorithm. If thereceived signal meets the criteria, the fault category would be assignedaccordingly.

Predetermined signal criteria for compression faults 318 may be based ona type of noise pattern and/or a rate of change of the raw signal, i.e.,typically downward. Compression faults are generally not preceded bypost-prandial rises, which are typically associated with a rise insignal accompanying ingestion of a meal. Other exemplary signal criteriafor compression faults are that the same tend to be more binary, fromone state to another, and not a smooth transition. Other signal criteriathat may be examined in the context of compression faults are forsignals that appear to follow patterns not associated with physiologicalchanges. Predetermined criteria for clinical context information forcompression faults may include the time of day, e.g., night time, when asleeping user may roll onto their sensor, as well as accelerometer data,which may also indicate sleeping, or heart rate information, which maybe slower for a sleeping user, as well as impedance data. As an exampleof compression in an intravenous system, where the glucose sensor isplaced intravenously, increased impedance can result from the sensorresting against the wall of the blood vessel, for example, producingnon-glucose reaction rate-limiting noise due to oxygen deficiency. Theuse of impedance data in determining clinical context information isexplained more fully in U.S. Patent Publication No. US-2012-0265035-A1,owned by the assignee of the present application and herein incorporatedby reference in its entirety. Exemplary uses of impedance data, as wellas devices to calculate impedance, are described below.

Other data that may be employed as predetermined clinical contextcriteria include whether a meal has been recently ingested, or whetherinsulin has been recently delivered, as often compression faults are notpreceded by a meal or medicament delivery.

Another fault category mentioned above pertains to early woundresponses, one variety of which is a temporary wound healing response,termed “dip-and-recover”. Without wishing to be bound by theory, it isbelieved that dip-and-recover may be triggered by trauma from insertionof the implantable sensor, and possibly also from irritation of thenerve bundle near the implantation, resulting in the nerve bundlereducing blood flow to the implantation area. Alternatively,dip-and-recover may be related to damage to nearby blood vessels,resulting in a vasospastic event. Generally any local cessation of bloodflow in the implantation area for a period of time leads to a reducedamount of glucose in the area of the sensor. During this time, thesensor has a reduced sensitivity and may be unable to accurately trackglucose. Thus, dip-and-recover typically manifests as a suppressedglucose signal. Dip-and-recover often appears within the first day afterimplantation of the signal, most commonly within the first 12 hoursafter implantation. Importantly, dip-and-recover normally resolveswithin 6-8 hours. Identification of dip-and-recover can provideinformation to a patient, physician, or other user that the sensor isonly temporarily affected by a short-term physiological response, andthat there is no need to remove the implant as normal function willlikely return within hours. Additional details may be found in U.S.Patent Publication No. US-2014-0005509-A1, owned by the assignee of thepresent application and herein incorporated by reference in itsentirety.

Exemplary signal criteria which may be employed to detectdip-and-recover faults include: a severe decline in signal, indicatingthe physiological conditions noted above, data about time since implant,as well as internal sensitivity measurements. Patterns may also beemployed, where such patterns have been previously identified with suchfaults. A signal repeating such a pattern may be inferred to beindicative of a dip-and-recover fault.

Exemplary clinical context criteria which may be employed to detectdip-and-recover faults include pattern analysis, where the base patternis defined by a clinical glucose profile for the patient. Currentsignals can be compared against such patterns to determine whether thecurrent signals are outside normal glucose patterns for the patient.Patterns may also be established and used to determine if the patient isat a higher risk for wound response type faults, e.g., does the patienthave a pattern of encountering such faults.

Besides dip-and-recover, other wound responses may also be the cause offaults and thus can be categorized within their own category or as partof a broader wound effect category. Appropriate responsive processingcan then be defined for such faults. Exemplary signal criteria for otherwound responses include impedance measurements between the workingelectrode and an external electrode to measure increases inelectrochemical impedance between the physiological environment and theworking electrode. Such impedance measurements are described in greaterdetail elsewhere.

In another exemplary fault category, a local effect at the sensor mayprohibit the analyte such as glucose from being measured properly.Examples of this type of fault or error include those in which themembrane of the sensor has been deleteriously affected. In general,however, such faults are characteristic of sensors nearing an“end-of-life” period. For example, biofouling can cause such a fault. Inthis case, exemplary signal criteria may include the amount of timesince sensor implantation, as well as certain characteristic noisepatterns. Other criteria include increased noise at higher glucoselevels compared to that at lower glucose levels. In yet other signalcriteria which may be employed to detect faults due to such localeffects of the sensor, an impedance measurement between the workingelectrode and an external electrode may be employed to measure increasein electrochemical impedance between the physiological environment andthe working electrode. Comparative responses at different electrodepotentials may also be employed.

Besides biofouling, oxygen noise may similarly be a fault caused as alocal effect at the sensor or membrane. Exemplary signal criteria foroxygen noise include a number of episodes of a similar signalcharacteristic. This may be contrasted with, e.g., the biofouling faultabove, in which there are several “small” episodes before largerepisodes start appearing. In other words, in biofouling faults, thereare several episodes of lower frequency and duration before largerepisodes appear of higher frequency and longer duration. In general anincrease in the signal frequency over the sensor session may be acriterion of an oxygen noise fault.

In these “local effect” faults, the clinical context may also be used ina determination of how to respond. In one type of responsive processing,the monitor may only display or rely on glucose values at “low glucose”levels, e.g., those below 100 mg/dL, as noise is more likely at highglucose levels.

Another type of fault involves the sensor end of life (“EOL”). Inparticular, embodiments of continuous glucose sensors described hereinmay have a useful life in which a sensor can provide reliable sensordata. After the useful life, the sensor may no longer be reliable,providing inaccurate sensor data. The signs of EOL may be recognized andany resulting user safety or in convenience may be prevented. To preventuse beyond the useful life, some embodiments notify a user to change thesensor after it has been determined that the sensor should no longer beused. Various methods can be used to determine whether a sensor shouldno longer be used, such as a predetermined amount of time transpiringsince the sensor was first used (e.g., when first implanted into a useror when first electrically connected to sensor electronics) or adetermination that the sensor is defective (e.g., due to membranerupture, unstable sensitivity or the like). Once it is determined thatthe sensor should no longer be used, the sensor system can notify a userthat a new sensor should be used by audibly and/or visually prompting auser to use a new sensor and/or shutting down a display or ceasing todisplay new (or real-time) sensor data on the display, for example.

In some embodiments, a plurality of risk factors may be evaluated thatare indicative of sensor EOL, for example using risk factorinstruction(s), algorithm(s) and/or function(s). In general EOL symptomsare progressive, e.g., not all symptoms (or episodes) indicate sensorfailure. Each of the risk factors may be evaluated periodically orintermittently as often as with the receipt of sensor data (e.g., every5 minutes) or more intermittently (e.g., every few hours or every day).The risk factors can be iteratively determined, averaged or trended overtime and the results used in later processing. In some embodiments, theevaluation of one or more risk factors may be triggered by anotherevent, such as a trended error in BG (e.g., from outlier detection)meeting one or more criteria.

In some embodiments, detection of EOL may be achieved using acombination of methods that each individually detect of EOL signaturesor risk factors. The combination of methods or signatures may result inimproved specificity (e.g., low false positives). It should beappreciated that the EOL determination methods or algorithms can use acombination of the risk factors in determining EOL.

In some embodiments, suitable risk factors may be selected from the listincluding, but not limited to: the number of days the sensor has been inuse (e.g., implanted); sensor sensitivity or whether there has been adecrease in signal sensitivity (e.g., change in amplitude and/orvariability of the sensitivity of the sensor compared to one or morepredetermined criteria), including magnitude and history; noise analysis(e.g., EOL noise factors (skewness, spikiness, & rotations)), duration,magnitude and history, spectral content analysis, pattern recognition);oxygen (e.g., concentration and/or whether there is a predeterminedoxygen concentration pattern); glucose patterns (e.g., mean,variability, meal characteristics such as peak-to-peak excursion,expected vs. unexpected behavior such as after a meal if glucose is notrising as expected); error between reference BG values and EGV sensorvalues, including direction of error (whether BG or EGV is readinghigher as compared to the other); and measure of linearity of the sensor(or the lack thereof). Sensor linearity refers to a consistency of thesensor's sensitivity over a particular range of measurement (e.g.,40-400 mg/dL for glucose sensors). For example, when the sensor signalis reading low with low BG and high with high BG, linearity may beassumed vs. when the sensor signal is reading low with low BG but notreading high with high BG (not changing or increasing beyond a certainBG value), where non-linearity may be assumed (based on error betweenreference BG values and EGV sensor values).

One risk factor that may be useful in the determination of EOL is thenumber of days the sensor has been in use (e.g., implanted). In someembodiments, the number of days the sensor has been in used isdetermined based in part on using initial calibration data, sensorinitialization, operable connection of the sensor with sensorelectronics, user entered data, or the like. In some embodiments, thesystem may detect sensor restart and uses restart information in thedetermination of the days since implantation.

In some embodiments, when a certain threshold has been met, e.g., acertain number of days, the particular variable associated with thethreshold may be automatically used in the EOL function. For example, ifthe number of days the sensor has been in use is determined to be atleast 4 days, then the number of days the sensor has been in use isautomatically used and/or a simple yes/no indicator that the thresholdhas been met. In some embodiments, if the number of days the sensor hasbeen in use is at least ⅓ of the days the sensor is approved for use,then the number of days the sensor has been in use is automaticallyused. In other embodiments, if the number of days the sensor has been inuse is at least ½, ⅔, or ¾ of the days the sensor is approved for use,or the like, then the number of days the sensor has been isautomatically used. In some embodiments, the actual number of days thesensor has been in use is always used in the EOL function. In someembodiments, the EOL function is performed after a predetermined numberof days of sensor use.

Additionally or alternatively, time elapsed from insertion may be mappedto an EOL risk factor value (e.g., likelihood of recovery or probabilityof sensor failure in future) because the longer a sensor has been in usesince implantation, the more the sensor-tissue interface changes(bio-fouling) will likely impact sensor function. In one example, theEOL risk factor value is mapped to about 1.0 between days 1 and 5 andreduces gradually beyond day 5 reaching to 0.5 at day 8, 0.2 at day 10,and about 0.1 at day 14. Other values and thresholds may be used as maybe appreciated by a skilled artisan.

Another risk factor that may be useful in the determination of EOL issensor sensitivity or whether there has been a decrease in signalsensitivity (e.g., change in amplitude and/or variability of thesensitivity of the sensor compared to one or more predeterminedcriteria), including magnitude and history. In some embodiments, theprocessor module may be configured to determine if there has been a dropin signal sensitivity. For example, for some sensors, their sensitivitydrifts up or remains relatively flat over most of the life of thesensor, e.g., 3, 5 or 7 days. Towards the EOL, the sensitivity of thesensor to changes in glucose may decrease. This reduction may berecognized as a drop in sensitivity that occurs monotonically overseveral hours (e.g., 12 hours), either by determining: (a) a change insensitivity (e.g., m in raw_signal=m*glucose+baseline) or (b) areduction in sensor raw count signal. For example, the followingequation may be used:

If median (raw count over last 12 hours)−median (raw count over last12-24 hours)<2*standard deviation over the last 12 hours, then thesensor may be nearing EOL.

In some embodiments, other forms of signal descriptive statisticsrelated to signal sensitivity (e.g., median, percentiles, inter-quartileranges, etc.) may be used to detect EOL. In some embodiments, whetherthere has been a decrease in signal sensitivity involves a determinationthat compares a measured signal sensitivity against a predeterminedsignal sensitivity threshold or profile to determine if the measuredsignal sensitivity is within an acceptable range. The acceptable rangemay be based on a priori information, such as from prior in vitro and/orin vivo testing of sensors. In some embodiments the measured signalsensitivity is outside an acceptable range, then the signal sensitivitymay automatically be used in the EOL function. In some embodiments, themeasured signal sensitivity, a change in sensitivity and/or an indicatorof a predetermined sensitivity decline may be used as an input or avariable in the EOL function.

In some embodiments, the sensitivity variable in the EOL function isbased on a trend of sensitivity during a particular sensor session(e.g., during the life of the sensor in the host). For example, thedetermination of whether there has been a decrease in signal sensitivityincludes comparing a first measured signal sensitivity at a first timepoint against a second measured signal sensitivity at a second timepoint to determine if rate of change in the measured signal sensitivityis within an acceptable range. The acceptable range may be determined bya priori information, such as from prior in vitro and/or in vivo testingof sensors. In one example, a change of greater than 20% over one daymay be an indicator of EOL and useful as an input in the EOL detectionfunction. In one example, a rate of acceleration (e.g., rate of drop ofsensitivity) of greater than 20% over 12 hours may be an indicator ofEOL and useful as an input in the EOL detection algorithm.

In some embodiments, the rate of change of signal sensitivity may bedetermined based in part on a slow moving average of raw sensor data(e.g., counts). This embodiment takes advantage of the fact that formost patients, the average glucose over time (e.g., a few days or more)remain relatively constant; thus, a change in the average of the sensordata (e.g., uncalibrated (raw or filtered) over time (e.g., 2, 3, 4, 5,6, 7 days or more)) may be interpreted as a change of sensitivity of thesensor over time. The results of the slow moving average could be aquantifiable amount and/or simple yes/no indicators of a sensitivitydecline that may be useful as one input or variable into the EOLfunction.

For example, the processor module may use an average of the last x hours(e.g. for 24 hours), a rectangular window averaging or an alpha filterwith an exponential forgetting factor to compute the slow moving averageto evaluate sensor sensitivity over time. In one example of an alphafilter with exponential forgetting, ‘alpha’ may be used as follows:

parameter(n)=parameter(n−1)*(1−alpha)+new_info*alpha

wherein alpha defines how much of history one wants to remember (howsoon to forget). In the above equation, alpha is a “forgetting factor.”Alpha may vary between 0 and 1, and its value dictates how fast oldmeasurements are forgotten by the model. For values of alpha close to 1,the model adapts more quickly to recent measurements. For values ofalpha close to 0, the model adapts more slowly to recent measurements.The value of alpha may depend on the elapsed time since the sensor wasimplanted. If alpha is 0.01, then in 1/0.01 (i.e., time constant of 100)samples, 63% of previous information is forgotten. Accordingly, if asampling rate is 12 samples/hr, then 63% of the signal would beforgotten by 100 samples, e.g., ˜8 hours. In such an example, it wouldfollow that with three time parameters or constants, which is about 1day, only 5% (i.e., 0.37*0.37*0.37=0.05) of signal left from theprevious day would remain. It is further noted that the calculation maybe recursive or non-recursive.

In some embodiments, sensitivity loss may be indicative of EOL.Sensitivity loss may occur towards the sensor EOL due to physiologicalwound healing and foreign body mechanisms around the sensor or othermechanisms including reference electrode capacity, enzyme depletion,membrane changes, or the like.

In some embodiments, sensor sensitivity may be computed using ananalysis of uncalibrated sensor data (e.g., raw or filtered). In oneexample, a slow moving average or median of raw count starts showingnegative trends, the sensor may be losing sensitivity. Loss ofsensitivity may be computed by calculating a short term (e.g. ˜6-8hours) average (or median) of the sensor output and normalizing it bythe expected longer term (48 hours) average sensor sensitivity. If theratio of short term to long term sensitivity is smaller than 70%, theremay be a risk of sensor losing sensitivity. Loss of sensitivity may betranslated into an EOL risk factor value, for example a value of about 1until the ratio is about 70%, reducing to 0.5 at 50% and <0.1 at 25%.

Alternative computations for risk of EOL related to sensitivity may useexternal references such as glucose finger stick readings. In eithercase, specific estimated sensitivity loss may be transformed into EOLrisk factor values using functions described elsewhere herein.

In some embodiments, sensor sensitivity may be computed by comparingsensor data (e.g., calibrated sensor data) with reference blood glucose(BG). For example, calibration algorithms adjust the glucose estimatesbased on the systematic bias between sensor and a reference BG. EOLalgorithms may use this bias, called error at calibration or downwarddrift, to quantify or qualify EOL symptoms. The error at calibration maybe normalized to account for irregular calibration times and smoothed togive more weight to recent data (e.g., moving average or exponentialsmoothing). In some embodiments, EOL risk factor value is determinedbased on the resulting smoothed error at calibration. In suchembodiments, EOL risk factor value is 1 for all values of error atcalibration>−0.3, and reduces to 0.5 at error at calibration=−0.4, andto <0.1 for error at calibration=−0.6.

Another risk factor that may be useful in the determination of EOL isnoise based on a noise analysis e.g., EOL noise factor (skewness,spikiness, & rotations), duration, magnitude and history, spectralcontent analysis, pattern recognition, etc. In some embodiments, theprocessor module may be configured to evaluate the noise (e.g.,amplitude, duration and/or pattern) to determine if there is apredetermined noise pattern indicative of EOL. For example, typicalsensor EOL signature may include an increase in spike activity, whichcan be detected using various methods of spike detection (e.g., bycomputing the mean rate of negative change).

In some embodiments, the duration of the noise may be indicative of EOL.Some noise detection algorithms that may be useful are described infurther detail in U.S. Pat. No. 8,260,393, incorporated herein byreference in its entirety. In some embodiments, the inputs to thecalculation of noise duration risk factor metric are the noisecategorization of sensor data. For example, each raw sensor count may becategorized as clean, light noise, medium noise or severe noise based onthe relative magnitude of sensor and filtered sensor counts and theirderivatives. This information may be used to translate severe noiseduration (e.g., amount of sensor data that are in severe noise state)into a metric that reflects EOL risk. An assumption behind thecalculation of this metric is that sensor EOL manifests as episodes ifcontinuous noise is detected rather than intermittent noise of a fewsamples. Thus, EOL algorithm may penalize the longer duration noisemore. Thus, at each sample time, total duration of noise up to the pointis used to calculate the EOL risk factor value at that point.

In some embodiments, whether there is a predetermined EOL signature(noise pattern) involves a determination that includes evaluating themeasured signal using pattern recognition algorithms to determine andidentify predetermined EOL signatures in the sensor signal. For example,by comparing the measured sensor signal against a noise patterncharacteristic of end of noise, it may be determined if the recordednoise pattern is similar to the predicted noise pattern.

In other embodiments, the determination of whether there is apredetermined noise pattern (EOL signature) includes comparing themeasured signal against a predetermined noise pattern to determine ifthe recorded noise pattern is similar to the predetermined noisepattern. For example, the predetermined noise pattern may include aseries of specific negative spikes in a short time frame. Thepredetermined noise pattern may also include an increase in spikeactivity for a given time frame.

In one embodiment, threshold detection for rate of change may be used todetect upward or downward spikes. Spikes may be detected by various waysas may be appreciated by one skilled in the art. For example, point topoint difference and thresholding, sharpness filters, etc. For example,an algorithm or function may output a +1 for an upward spike and a −1for a downward spike. Using this spike data time series, one may useeither upward spike detection algorithms or downward spike detectionalgorithms or total spike detection (e.g., positive or negative spiketime series) algorithms.

In some embodiments, EOL detection using these spike detection functionsmay be achieved using a negative threshold on the moving average ofspike time series (e.g., 2 times negative spikes than positive) or athreshold (e.g. 3 or 4) on total spike activity showing a 3 to 4 timesincrease in total spike activity. Other forms of spike detection such asleast squares acceleration filters may be employed. In some embodiments,an EOL risk factor value may be determined to be 1 for a value of aspike metric <1, and reduced to 0.5 for a spike metric >2, and to <0.1for spike metric >5, and so on.

In addition to or alternatively, high frequency activity or patterns maybe used in EOL detection. For example, EOL signature patterns may show asignificant increase in high frequency activity when a power spectraldensity (PSD) or a Fast Fourier Transform (FFT) is performed on thesensor data. Normal glucose signal has very low frequencies (e.g., 0 and1.8 mHz). Consequently, a high pass filter or a band pass filter may beused to detect the EOL pattern associated with high frequency activity.

In some embodiments, a slow changing long-time scale average signal maybe used to normalize the data to enhance the reliability of detectionmethods, e.g., signal sensitivity or noise pattern. For example, byusing the following definitions:

Long_time_scale=long time (1-2 day) moving average or filtered rawglucose dataSignature=short term (˜4-6 hrs) filtered (any including spike detection)data

Normalized_Signal=Signature/Long_time_scale

Thresholds for normalized signal and duration constraints may be appliedto detect EOL signatures. Consequently, EOL may be detected if:

Normalized_Signal>Threshold for greater than certain Duration.

In some embodiments, the threshold and duration may be optimized toachieve specific sensitivity and specificity. Alternatively, having ashort duration constraint may be used to detect oxygen noise instead ofEOL.

In some examples, EOL noise may be determined to be sensor EOL specificbased on various algorithms that evaluate known EOL failure modesidentifiable on the signal. It may have large (>30% point to point drop)downward spikes, negatively skewed over the duration of an episode, withintermittent rapid rotations or oscillations, e.g., multiple peaks andvalleys or number of derivative sign changes. Noise discrimination canuse these features to identify if a sensor shows EOL symptoms anddepending on the magnitude and duration, can calculate the EOL riskfactor value from an episode, which may also be termed the noise factor.

Another risk factor that may be useful in the determination of EOL isoxygen (e.g., concentration and/or whether there is a predeterminedoxygen concentration pattern). For example, in some embodiments, theprocessor module may be configured to determine if there ispredetermined oxygen concentration and/or trend or pattern associatedwith the oxygen concentration. Any oxygen sensor useful for quantifyingan oxygen concentration may be useful here, separate from or integralwith the sensor. In an electrochemical sensor that includes apotentiostat, pulsed amperometric detection can be employed to determinean oxygen measurement. Pulsed amperometric detection includes switching,cycling, or pulsing the voltage of the working electrode (or referenceelectrode) in an electrochemical system, for example between a positivevoltage (e.g., +0.6 for detecting glucose) and a negative voltage (e.g.,−0.6 for detecting oxygen). In some embodiments, oxygen deficiency canbe seen at the counter electrode when insufficient oxygen is availablefor reduction, which thereby affects the counter electrode in that it isunable to balance the current coming from the working electrode. Wheninsufficient oxygen is available for the counter electrode, the counterelectrode can be driven in its electrochemical search for electrons allthe way to its most negative value, which could be ground or 0.0V, whichcauses the reference to shift, reducing the bias voltage such asdescribed in more detail below. In other words, a common result ofischemia will be seen as a drop off in sensor current as a function ofglucose concentration (e.g., lower sensitivity). This happens becausethe working electrode no longer oxidizes all of the H2O2 arriving at itssurface because of the reduced bias.

In some embodiments, a non-enzyme electrode or sensor may be used as anoxygen sensor. In an exemplary dual working electrode sensor, havingenzyme and no-enzyme working electrodes, the non-enzyme electrode may beused as an oxygen sensor by changing the bias potential from a positivevalue (e.g., 600 mV-800 mV) to a negative value (e.g., negative 600mV-800 mV). At this potential, dissolved oxygen is reduced and givesrise to a negative current through the non-enzyme electrode. In someembodiments, by switching the bias potential on the non-enzyme electrodebetween the indicated positive and negative biases, a bi-functionalelectrode results. When a positive bias is applied, the current may berelated to baseline and when a negative bias is applied, the current maybe related to the local oxygen concentration.

It is known that glucose oxidase based sensors are limited by the amountof oxygen present. When the oxygen level reduces below a thresholdvalue, the enzyme electrode current drops (“oxygen starvation”) whilethe glucose concentration remains constant. This oxygen starvation mayresult in reduced accuracy, as lower than actual glucose levels may bereported. Oxygen starvation can occur late in sensor life, such as whenthe sensor is encapsulated in the subcutaneous environment.Consequently, being able to measure oxygen allows the detection of thisencapsulation and EOL for the sensor.

In some embodiments, whether there is a predetermined oxygenconcentration pattern involves a determination that includes reviewingthe oxygen concentration pattern to see if the oxygen concentration isappropriate. For example, an oxygen concentration pattern that showsreduction in oxygen availability over time may be indicative of EOL ofthe sensor.

Another risk factor that may be useful in the determination of EOL isglucose pattern (e.g., mean, variability, meal characteristics such aspeak-to-peak excursion, expected vs. unexpected behavior such as after ameal if glucose is not rising as expected).

Still another risk factor that may be useful in the determination of EOLis error between reference BG values and corresponding calibrated sensordata (estimated glucose value, or EGV), including direction of error(e.g., whether BG or EGV is reading higher as compared to the other)and/or utilizing flagged outliers. In some embodiments, the system mayidentify discrepancies between reference values (e.g., BG) and sensorvalues (e.g., EGV). For example, when there is a large difference in thereference values and sensor values, something is likely not workingcorrectly. In certain embodiments, a large discrepancy between thereference values and sensor values may indicate end of sensor life.While not wishing to be bound to any particular theory, this is believedbecause the sensor is reading either higher or lower than it should. Insome embodiments, the direction of the error, for example whether the BGis higher or lower than the EGV is used as an EOL indicator. Stillanother risk factor that may be useful in the determination of EOL is ameasure of linearity of the sensor (or the lack thereof). As describedabove, sensor linearity refers to a consistency of the sensor'ssensitivity over a particular range of measurement (e.g., 40-400 mg/dLfor glucose sensors).

In some embodiments, the processor module is configured to evaluate thevarious risk factors to provide EOL risk factor values, which mayinclude simple binary (yes/no) indicators, likelihood or probabilityscores (e.g., relatively scaled or percentages) and/or actual numbers(e.g., outputs of the various tests). The risk factor values may bescaled if the weights used in the algorithm are modified.

In some embodiments, the processor module is configured to runprobability functions to determine a probability of EOL and/or alikelihood of recovery for one or more of the plurality of EOL riskfactors. In some embodiments, risk factors are mapped to a score (e.g.,from 0 to 1) based on one or more parameters. The score may be mapped byfunctions, which translate a particular risk factor or set of riskfactors to an EOL risk factor value, indicating for example, apossibility of the sensor to recover from a particular risk factor fromEOL. Other methods of translating risk factor outputs into EOL riskfactor values may be used as is appreciated by a skilled artisan, suchas by using one or more criteria, algorithms, functions or equations.

In some embodiments, risk factors are fuzzified using pre-determinedmembership functions in order to quantify their propensity to indicateEOL. As used herein, a membership function defines the degrees to whicha condition is satisfied, or a degree to which a value belongs to afuzzy set defined by that function. In binary logic, a number wouldeither satisfy a condition fully or not at all; in fuzzy logic, a numbercan satisfy a condition to a certain degree described by a membershipfunction.

As an example of a binary indicator function, a noise level is comparedto a hard threshold, such as “5”; any value below 5 (such as 4.9) istreated as being noise-free and any value above 5 (such as 5.1) istreated as having an unacceptable level of noise. As an example of afuzzy membership function, a sigmoidal shape may be used to define asmooth transition in the evaluation of the noise levels. The inflectionpoint of the curve is set at 5, so there is no discontinuity at thatpoint. Thus, the same values of noise (4.9 and 5.1) as above are nowtreated very similarly. Fuzzification is the determination of the degreeto which a value belongs to a fuzzy set defined by a particularmembership function.

In some embodiments, each of the plurality of risk factors is partiallyindicative of the EOL of the sensor if each variable is determined tomeet a threshold. In some embodiments, if at least two of the pluralityof risk factors are determined to meet a threshold, then the combinationof the at least two risk factors is indicative of the EOL of the sensor.

The system may be configured to determine an EOL status. In oneembodiment, a likelihood or probability analysis may be used todetermine an EOL status of the sensor. The outputs of the risk factorsbecome inputs into an EOL determination process. For example, theoutputs of the risk factors may be mapped to EOL risk factor values, forexample values from 0 to 1, probability or likelihood scores, actualvalues (outputs from the risk factor evaluation(s)), and/or the like.The EOL risk factor values then become inputs into the EOL determinationfunction, whereby the risk factors may be weighted or otherwiseprocessed using a probability analysis, decision matrix, varioussubroutines or the like, to determine an actual EOL indicator, aprobability (or likelihood) of EOL, a predicted time to EOL, or thelike. Probability functions, decision functions, various subroutines, orthe like may be implemented as the EOL determination function as isappreciated by one skilled in the art.

In one embodiment, decision fusion may be used as the function throughwhich the various inputs are processed. Decision fusion may provide aFused Bayesian likelihood estimate based on sensitivity and specificityof individual detector algorithms associated with each input orvariable. Suitable risk factors are measured and fused together todetermine whether or not a sensor has reached EOL. A decision can bemade for “yes” EOL or “no” EOL based on each individual risk factor. Forexample, if sensor sensitivity has decreased by more than Δm over someamount of time Δt then “yes” EOL otherwise “no”, or if the sensor hashad severe noise (above a predetermined threshold level) for more than12 hours of the last 24 hours then “yes” EOL, otherwise “no”.

The individual decisions can be combined into a single Bayesianlikelihood value that can be used to make the best final decision aboutEOL, using the sensitivity and specificity of each variable in detectingEOL. First, each decision is converted to a likelihood value using thefollowing equation:

${\lambda (d)} = \frac{P\left( d \middle| H_{1} \right)}{P\left( d \middle| H_{0} \right)}$

where d is a binary decision of 0 or 1 (no or yes), H1 is the case thatEOL is present, H0 is the case that EOL is not, and P( ) is theprobability function. In practice, this means for a “yes” decisionλ=sensitivity/(1-specificity), and for a “no” decisionλ=(1−sensitivity)/specificity. For an individual variable test with highsensitivity and specificity, λ will be very high for a decision of 1 andvery small for a decision of 0.

In some embodiments, the individual likelihood values are multipliedtogether for a final fused likelihood value that takes into account theability of each individual variable to separate EOL from non-EOL. Thus,more sensitive and specific tests will be given greater weight in thefinal decision. A threshold may be determined empirically for the finalfused likelihood values to achieve the best separation of EOL andnon-EOL.

In some embodiments, linear discriminant analysis (LDA) may be used asthe EOL determination function, by taking the input variables andproviding an output decision.

In some embodiments, when EOL inputs or variables are fuzzified usingpre-determined membership functions, resulting degrees of membership forall data quality metrics are scaled according to pre-determined weightsand combined to produce an indicator of the overall quality of thecomputed glucose value. The weights may be applicable to every metricand may show how indicative a metric is of EOL. These embodiments mayuse several fuzzy logic concepts such as membership functions andfuzzification, as described above, to determine the degree of severityof each data quality metric. The result of the EOL detection may be aconfidence indicator that determines a likelihood of EOL beyond a simplepass/fail criterion.

In some embodiments, EOL status may be determined based on likelihood ofa sensor not recovering from an event, rather than occurrence of anevent; the likelihood of a sensor not recovering may be defined as thestate when a sensor is likely to be no longer accurate or has longepisodes of noise (e.g., based on risk factor evaluation(s)). The EOLindicator may also indicate a possibility of recovery (e.g., when theepisode may be transient rather than terminal). In some embodiments, thesystem may be configured to determine a likelihood of recovery and/ormonitor the sensor or sensor data over the next x hours to determinewhether the sensor may recover from the EOL symptoms (e.g., thelikelihood of sensor providing accurate data to user in next 24 hours).In some embodiments, the sensor will only be determined to be at EOL ifa high probability of sensor not tracking glucose in the future (e.g.,24 hours) or not showing glucose at all for several hours (e.g., 12hours) is determined (e.g., inaccuracy may be determined by a comparisonof EGV with reference BG using a standard (e.g., within 20% or 20mg/dL)).

The system may optionally be configured to monitor the risk factors(e.g., for example more frequently after EOL indicator determines alikelihood of EOL) to determine whether it is more than likely that thesensor will not recover from the EOL determination. Functions oralgorithms suitable for determining whether a sensor will recover fromEOL may be selected from those known by one of skill in the art. Forexample, determining whether a sensor will recover may be a 0 to 1scaling based on an evaluation of one or more risk factors.

In some embodiments, the system may be configured to determine, based onrecent history, the likelihood of a sensor to recover from the EOLdetermination. For example, the EOL determination function may determinethe EOL status is more than likely if there is a high probability thatthe sensor will not track glucose in the future or that the sensor isnot detecting glucose at all for extended durations. Extended durationsmay include time periods exceeding 12 hours. In some embodiments, theprocessor module is configured to suspend display of sensor data duringverification or determination of a likelihood of recovery, after whichthe processor module may be configured to either re-allow display ofsensor data if it is determined that the sensor has recovered from theEOL symptoms.

In some embodiments, intermittent signs of EOL may be used to turn onadvanced signal filtering techniques. Such filtering techniques aredescribed, for example, as described in more detail in U.S. Pat. No.8,260,393, which is incorporated herein by reference in its entirety.

In some embodiments, the monitoring application may initiate a countdowntimer which, upon expiration, requires or suggests insertion of a newsensor.

Additional details of “end-of-life” sensor issues are found in U.S.Patent Publication No. US-2014-0182350-A1, owned by the assignee of thepresent application and herein incorporated by reference in itsentirety.

Returning to FIG. 18 and in particular faults 316, faults may becategorized as system errors, e.g., resulting in erroneous signalartifacts. In these faults, system errors such as those related to thesensor, connections within the sensor or sensor electronics, transmittererrors, and the like, may cause a variety of deleterious signalartifacts resulting in an unreliable analyte reading. One subcategorization includes a seal failure that can lead to a water spike.Exemplary predetermined signal criteria that may be employed to testsignals for such faults include a change in the raw signal over a shortperiod of time, e.g., a rapid positive rise. Other signals which may beused in this fault discrimination include the temperature of the sensor,which may indicate the patient has entered a shower or hot tub. Otherexemplary signal criteria include time of day and/or signals fromtemperature sensors. It should be noted here that temperature is beingemployed in this context in the determination of clinical contextinformation, and is being employed for the purpose of determination ofclinical context, as opposed to use of the temperature per se, e.g., fortemperature compensation. Thus for use as clinical context information,a measured temperature is generally compared to a clinical contextcriterion to determine clinical context information. The determinationas noted often requires additional clinical context information to avoidambiguity. For example, if the temperature of the sensor (the measuredsignal) rises to a certain value or rises a predetermined thresholdabove a certain value (the clinical context criterion), e.g., 5°, thensuch may indicate showering (the clinical context information). Whenconsidered along with other clinical context information, e.g., patterndata, such as a regular time of day for a shower, and/or signal data,e.g., a spike, may lead to the unambiguous evaluation of a water spike.Another sub categorization includes faults related to electrostaticnoise, which may be caused by the rubbing of clothing on the sensor orelectronics patch, especially during repetitive activities and dryweather. Signal information which may indicate such a fault includesanalysis of the frequency content of the signal and comparison withfault discrimination criteria. Clinical context data may includeindications of user movement or exercise, e.g., gleaned fromaccelerometer data on the transmitter or on an accompanying mobiledevice in data communication with the monitoring application.

Another sub categorization includes faults related to motion artifacts,such as those caused by exercise or other motion around the sensor patcharea. Such faults may be especially common if the patient wears thesensor on their back upper arm or other similar location, as suchlocations are generally more susceptible to motion affecting the sensorsite. Signal criteria which may be used to discriminate such faultsinclude analysis of the signal shape itself, including morphological,time, frequency, and distribution aspects. Clinical context data forsuch faults include detection of exercise or activity level, such as maybe gleaned from an accelerometer, GPS, user input, or the like.

A further sub categorization includes faults related to drift. Forexample, the drift may be in either of the quantities m or b, wherey=mx+b, which is a regression equation where the slope M representsensitivity of the sensor and the intercept b represents a background oroffset. Signal criteria to discriminate such faults may includemeasuring a potential at a first time and measuring a potential at asecond time, at the same electrode, and determining if a drift in m or bhas occurred. Calibration errors may also indicate such drift faults.

Yet another sub categorization includes faults relating to poorconnections and/or broken wires. A signal criterion which may be used todiscriminate such faults includes detecting high-frequency noise, whichmay be characteristic of poor connections or broken wires. Fuzzy logicmay also be employed to determine the type of noise, particularly as thesame may be distinguished from other sorts of noise, e.g., during steepchanges in rates of change.

Other categorization schemes will also be understood. For example, andreferring to the flowchart 299 of FIG. 19, if the fault discriminationroutine determines that the signal can be corrected (step 301), e.g., bya prediction or other sort of signal processing, then the fault may becategorized as a “Category 1 fault” (step 303) and signal processingappropriate for such may be applied. If not, the routine may determineif the display should be suspended (step 305), and if so the fault maybe categorized as a category 2 fault (step 307), and display suspended.If display is not suspended, the routine may determine if user inputwould help correct the fault or discriminate the fault (step 309), andif so the fault may be categorized as a category 3 fault (step 311). Inthis case, such user input may be prompted for. Finally, the routine maydetermine if the sensor, the sensor electronics, monitoring device, or acombination of the same should be replaced (step 313). If so, the faultmay be categorized as a category 4 fault (step 315). As with the above,for all of these categories, predetermined signal criteria and apredetermined clinical context criteria would be defined which, if met,would cause the fault to be associated with the one or more categories.It will be understood that the above steps may be performed in varyingorder.

As yet another example of a categorization scheme, a lookup table may beused by the routine which keys off certain signal behaviors and clinicalcontext information. For example, referring to FIG. 20, a lookup tableis shown which keys off of signal behaviors and two pieces of clinicalcontext information. Exemplary signal behaviors and clinical contextinformation are shown, but it will be understood that the limited numbershown are for clarity and that generally many others may also beemployed.

Similarly, a hierarchical approach to fault discrimination orcategorization may be applied. Referring to FIG. 21, faultdiscrimination or categorization may occur by listing faults in theirorder of occurrence, e.g., from the most common fault to the leastcommon fault, along with appropriate signal analysis and clinicalcontext criteria for each respective fault. The algorithm or routine maythen, starting with the most common fault, determine if the currentsignal analysis and clinical context data meet the criteria. If so, theanalysis may end there and the fault or fault category may be determinedfrom the table. If not, the analysis may continue to the next mostcommon fault, again applying the current signal analysis data andclinical context information to the predetermined criteria for the givenfault. By the process of elimination, the fault or fault category may bedetermined. As the faults are listed in order of their prevalence, sucha hierarchical approach may lead to a rapid or in some cases optimizedfault discrimination or categorization.

Yet another approach to fault discrimination or categorization includesuse of “decision fusion” methods. In these methods, faultdiscrimination, categorization, or determination may be made frommultiple inputs. Decision fusion uses a statistical model to optimallycombine information from multiple inputs, e.g., clinical context dataand signal analysis data, and produces a likelihood value that the datais associated with a particular fault or fault category. Such methodsare particularly useful in combining heterogeneous inputs, like glucoserate of change and number of receiver button presses of the last twentyminutes, into a single likelihood scale. Prior information on thesensitivity and specificity of each input in predicting the undesiredevent, e.g., hypoglycemia, is used to determine how much weight to giveeach input in the final output.

Additional details about decision fusion methods are provided in U.S.Patent Publication No. 2014-0182350-A1, owned by the assignee of thepresent application and herein incorporated by reference in itsentirety.

While the above description has discussed exemplary categorizations andfault types, as well as discriminating the same, it will be understoodthat any method for identifying a fault of a particular type or categorymay be used, whether qualitative or quantitative.

Responsive Signal Processing

Various types of steps of responsive signal processing 328 areillustrated by the diagram 326 of FIG. 22. Steps taken in a givencircumstance depend on the discriminated fault and the clinical contextinformation, and particular examples are given below. The following arean exemplary but non-exhaustive list of such steps.

First, as discussed above in connection with faults that are detectableand treatable without user intervention, a step 332 may be employed inwhich filtering is adjusted or a prediction of an analyte concentrationis made. These steps may be performed for number of reasons, includingcompensating for a time lag due to the fault or due to signal processingto compensate for the fault.

In the case of noise filtering, the same may be reduced during theclinical context of a high rate of change in analyte concentration. Inthis way, if an analyte such as glucose has a concentration that israpidly changing, the reduced filtering will cause additional datapoints to be taken or received so as to obtain a more accurate pictureof the user's glycemic state. In this way, the values during the rapidchange may be more closely and rapidly followed, thereby enabling a morerapid response, where a response is called for. Conversely, filteringmay be increased during the clinical context of a low rate of change ofanalyte concentration, particularly in high noise states. In alternativeimplementations, filtering may be enhanced by the use of fuzzy filteringas described above as well as below. Other techniques may also beemployed in other implementations, including the use of regression andresiduals, as described below in the context of FIG. 37.

In more detail, filtering may be reduced during a clinical context of alow analyte concentration, e.g., a hypoglycemic state. In this way, thereduced filtering causes data points to be processed in a more timelyfashion, i.e., with relatively less time lag as compared to morefiltering. The situation is seen in FIG. 23A, in which a clinicalglucose value is seen approaching a hypoglycemic state. The noise valueis relatively stable. However, as the glucose value approaches or entersthe hypoglycemic state, the level of filtering is lessened to provide amore responsive system as required to detect and treat hypoglycemicevents.

Another situation in which step 332 may be applied are those in whichthe noise is of a specific predetermined type or severity. In thesecases, even without consideration of the clinical context, filtering maybe adjusted, e.g., to increase filtering of particularly noisy signalsor decrease filtering of especially smooth ones. This situation isillustrated in FIG. 23B, where again filtering is lessened during aperiod of hypoglycemia. The filtering is seen to go back to a normalvalue when the user is no longer in the hypoglycemic state. In addition,as the raw signal encounters greater levels of noise, e.g., where theuser is running or jogging, an even heavier filter is applied. Ingeneral the filtering may be balanced based on noise type and severity,in addition to clinical context information such as the rate of changeof the analyte concentration.

In a related step for responsive processing using signal processing ormanipulation, the sampling rate may be altered as noted above withrespect to FIG. 9. In particular, the sampling rate may be adjusted to afaster or slower rate to accommodate various fault situations. Forexample, if the fault is indicated by the sudden upward or downwarddirection of the raw signal, sampling may be automatically increased toallow additional data to be received, allowing a better understanding ofthe underlying phenomenon.

In another step of responsive processing, the bias potential may bechanged to one that might be less susceptible to certain fault types,e.g., less susceptible to noise.

Returning to FIG. 22, another type of responsive processing is for themonitoring device to enter a self diagnostics mode (step 334). In thismode, the monitoring device may run a number of routines to test itself,and thereby to attempt to determine the source of a fault. In some casesthe fault may be automatically remedied, and in other cases the faultmay require user intervention. The level of user intervention may vary,e.g., from a relatively nonintrusive step of performing a calibrationstep to a more drastic step calling for replacement of the monitoringdevice. In self-diagnostic modes, a step of sweeping may be performedacross varying potentials to determine proper behavior of the sensor,e.g., to detect a reference bias shift indicative of reference electrodedepletion or instability due to ischemic conditions. Self diagnosticsroutines may also be run with transient signals, pulsed signals, or thelike, and the same may be scanned over various frequencies. Such a modemay also be employed to test fault behavior at different potentials, asfaults may behave differently at different electrode potentials or whenthe electrode potentials are switched, e.g., as evidenced by a transientresponse or decay curve. Self diagnostics routines may also test thetransmitter, and may further perform comparisons of resolutions in theslow versus fast sampling techniques noted elsewhere.

A further type of responsive processing is to perform a step ofcompensating for the fault (step 336). For example, one type ofcompensation is to provide a predicted, forecasted, or expected analyteconcentration value over the duration of the fault. For example, if anupward spike is seen in the raw signal value, but the clinical contextindicates a high glucose value or euglycemia, and if other clinicalcontext information indicates that the time of day is the morning, awater ingress fault such as may be caused during a morning shower may beinferred and the actual glucose value replaced with a predicted one,based on the value seen before the water ingress and, e.g., otherclinical context information. Redundant signals and average signals maybe used similarly. It is noted that the use of forecasting may depend oncontext, e.g., whether the user is sleeping versus ingesting a meal.

Forecasting may also be employed to compensate for time lag based onglycemic state. In particular, and as noted above, a time lag can leadto deleterious results, particularly during times of high rate ofanalyte concentration change and at low overall analyte concentrationvalues. Accordingly, the use and display of forecasted or predictedvalues may be advantageously employed during these times.

However, in some clinical context the use of predicted values may bediscouraged. For example, fault compensation by predicted values may besafe at high glucose values but may be more dangerous at low glucosevalues. In these situations, rather than performing a compensation step,the clinical context may indicate that the responsive processing shouldcall for a finger stick measurement to be taken.

Besides providing a prediction, faults may be compensated for by the useof specific algorithms. For example, to compensate for the discriminatedfault of compression, a max average algorithm may be employed,particularly where the clinical context indicates that the time of dayis night time and the patient is above a certain clinical glucose value.

Other types of responsive processing will also be seen. For example, inmulti-sensor systems (e.g., multi-electrode systems), described ingreater detail below, redundant signals may be received and employed asnoted above, and in such systems effects due to local sensorsurroundings may be isolated and thereby compensated for. In yet anothertype of responsive processing, where a large amount of noise is presenton the signal, the CGM value may be turned off and a very heavy oraggressive filter applied. The CGM may still provide a report,particularly on trends, but such would only include those seen throughthe aggressive filter. For an actual value of blood glucose, users maybe prompted to use a finger stick.

The above-noted steps 332, 334, and 336 may be performed withoutsignificant user input, or even user knowledge that the steps areoccurring. By contrast, many implementations of steps 338 and 342 belowrequire user knowledge and in some cases user intervention.

For example, another type of responsive processing is to alter thedisplay of the monitoring device (step 338). In this way, the user canbe alerted to the situation, e.g., that the current glucose value isunreliable, and the user may further be prompted to input additionalinformation which may be employed by the algorithm in furtherprocessing, e.g., to enter meal or exercise information. The user mayalso be alerted to perform certain steps to alleviate the fault. Forexample, during high noise periods, additional calibrations may berequested by the system, particularly if the user is near importantvalues, such as hypoglycemic and hyperglycemic thresholds. Similarly, ifthe fault is discriminated as a compression fault, the user may bedirected to relieve the compression from the sensor. The user may alsobe queried as to various potential causes of a discriminated fault,e.g., “WERE YOU LYING ON YOUR SENSOR?”. In certain implementations, theuser may be prompted to perform a finger stick to determine their actualblood glucose value, especially when the CGM is detecting a low glucoseconcentration value. The results of such measurements and queries may befed back into a user profile and used later for personalized faultdiscrimination routines. In other words, adaptive or machine learningmay be triggered and the system may thus become alerted to faultscharacteristic or typical of a given patient, enabling even more rapidactionable alerts.

In yet another implementation, the output could be provided with anindicator of the confidence with which the algorithm has computed theanalyte concentration (step 339), e.g., a confidence level, a “faultindex” indicating the type or severity of the current fault, or thelike. Colors, of the display or the background, may be employed todiscreetly indicate to the user data confidence. The output may bedelayed, or a cautionary notice placed on the output. A range ofpotential analyte concentration values may be provided to indicate theinherent uncertainty in the data. Alert and alarm conditions may bemodified or adjusted to account for uncertainties in the data due tofaults, e.g., may be adjusted to more conservative values.Alternatively, certain alarms may be suspended to alleviate false ordistracting warnings. Moreover, the output may be changed based on theconfidence in data quality, e.g., via a confidence metric.

In more detail, there are various sources of inaccuracy and imprecisionthat may be present in an analyte monitor. These include noise and/orimprecision in the raw sensor signal, reference and calibration error,compartmental effects and analyte reference temporal mismatch,physiological foreign body responses, and transient electrical,chemical, and biological interference. These sources of error can bequantified by examining prior sensor data and/or using Monte Carlo-basederror budgeting models. The combination of the errors results ininaccurate CGM glucose readings, but the degree of inaccuracy varieswith varying conditions. For example, current subcutaneous sensors arewell-known to have less accuracy during the first day of use compared tolater days. Some sensors tend to perform less accurately during fastrates of change of glucose (as compared to steady state glucose trends).A cumulative accuracy measure fails to account for differences inaccuracy between individual points. Errors can be visualized andexamined in detail during post processing steps by utilizingBland-Altman style plots or a Clarke Error Grid, but such tools aresometimes difficult to use, and are generally retrospective in nature.

One way of determining a confidence indicator is by the followingtechnique. First, raw sensor data and diagnostic information arecollected. Diagnostic information may include signal noise levels, localtrend information, data from auxiliary sensors, or the like. Thisinformation is used in normal glucose value calculations, but can alsobe used to evaluate the confidence in the data. In the next step, allpieces of the data are evaluated according to empirical and/or adaptivecriteria in order to determine the quality of various aspects of thesignal, e.g., noise level, agreement with prior measurements, or thelike. Intermediate calculations are performed, such as for sensorsensitivity and baseline, sensor working conditions, and so on.Operational characteristics are also evaluated according to separatesets of criteria to provide additional information. In this step,significant information is gathered and qualified to provide theconfidence technique with enough to produce a good estimate ofconfidence.

Data quality metrics for all applicable pieces of information are thenincluded using predetermined “membership functions” in order to quantifytheir propensity to cause inaccuracy in resulting glucose values. In thetechnique of fuzzy logic, such is termed “fuzzification” or being“fuzzified”. Resulting degrees of membership for all data qualitymetrics are scaled according to predetermined weights and combined toproduce an indicator of the overall quality of the computing glucosevalue. The weights are applicable to every metric, and show howindicative the metric is of an inaccurate glucose value. For example,relative contributions of different metrics to an overall confidenceindicator may be as follows. A recent glucose value may have a qualityof 19% in its propensity to cause inaccuracy, while the glucose trendconsistency may indicate a 34% confidence indicator contribution,glucose signal stability may contribute 28%, and the pressure signal maycontribute 19%.

The technique can then determine the degree of severity of each dataquality metric. In the terms above, a membership function defines thedegrees to which a condition is satisfied, or the degree to which avalue belongs to a fuzzy set defined by that function. In conventionalbinary logic, a number will either satisfy a condition only or not atall; in fuzzy logic, the number can satisfy a condition to a certaindegree described by a membership function. Fuzzy logic can then beemployed to determine whether a level of noise in the signal is a causefor concern.

FIG. 23C indicates a fuzzy membership function. The sigmoid shapedefines a smooth transition in the evaluation of the noise levels. Theinflection point of the curve is set at 5, so there is no discontinuityat that point. Thus similar values of noise, e.g., 4.9 and 5.1, aretreated very similarly. Fuzzification is the determination of the degreeto which a value belongs to a fuzzy set defined by a particularmembership function, and the figure demonstrates the results offuzzification of the values 4.9 and 5.1 using the provided membershipfunction. The resulting membership values of 0.45 and 0.55 reflect boththe levels of noise relative to a threshold in the similarity betweenthe two levels of noise. Use of such fuzzy logic improves the accuracyof the system and the selectivity of the algorithm in marking the pointswith the potential to be inaccurate as unacceptable. The technique mayincrease the number of glucose values that are both accurate anddisplayed and decrease the number of values that are accurate but areerroneously blanked. Such may also help reduce the incidence of falsealarms and provide the user with actionable alarms to aid in resolvingthe issues that arise with the data in the system.

Besides including such in the determination of noise, a confidence levelindicator can be provided along with the displayed glucose value (step339), and the same used for calculations. Advantages include that theconfidence level indicator can determine whether a glucose value isacceptable or not, beyond a simple pass/fail criterion. Such may aid ineliminating single point failures as well as making analyte monitoringalgorithms more intelligent in their classification of data.

Finally, in the step 338 of altering the display, it is noted that theoutput display may vary based on the clinical context information, evenwith a common value of the analyte concentration.

Returning again to FIG. 22, as yet another example of responsiveprocessing, the monitoring device may be caused to switch betweentherapeutic modes (step 342). In this implementation, a fault may causea closed loop or connected medicament pump to enter a mode where it isopen loop or only semi-closed loop. Similarly, the system may changefrom having a therapeutic data usability to having an adjunctive datausability. Rather than basing pump actions on the clinical glucosevalue, the clinical glucose value may be provided to the user and theuser may then control the pump action, or perform the affirmative stepof acknowledgment or validation of the pump action, where the user isgenerally taking into account other known data. For example, such resortto open loop processing may occur upon discrimination of adip-and-recover fault or a biofouling fault.

Similarly, the analyte monitor may be caused to enter a calibrationmode, e.g., one in which the same is calibrated against a blood glucosemeter calibration or the factory calibration. The calibration scheme mayalso be modified so as to affect the interpretation or weightings ofvalues determined by finger sticks or other measurements. In a relatedtechnique, the system may instruct the user to provide a blood glucosefinger stick value, but that calibration may be tagged as a known error,and the same employed for calibration purposes only until it isdetermined that the error or fault has been remedied, in which case theuser is cued to provide an additional calibration point, and the systemsubsequently ignores the previously-determined faulty calibration point.

Even without switching modes, one type of responsive processing is tomanage or control, or cause or instruct the user to manage or control,the interaction between devices involved with diabetes management, e.g.,meter, pump, CGM, and the like. In this way, the user may be instructedto more closely or to manually control interaction between devices suchthat faults on one device do not propagate and cause errors ondownstream devices. Such responsive processing may include reducing therisk threshold of insulin amounts, adjusting a default basal mode, andthe like.

Other types of responsive processing will also be understood. Forexample, a “flag” may be placed on the data to indicate the same is lessreliable. For certain data known to be faulty, even if the data is stillused, a weight attributed to the data may be lessened. Whatever thetype, a benefit and advantage to the responsive processing steps notedare that the same tend to extend the life of the sensor, by allowing thesensor to continue working until a permanent failure is detected. Thisresults in significant cost and convenience advantages to the user. Thisadvantage may be contrasted with prior sensors, that generally have ahard shut off after a predetermined number of days.

The above types of responsive processing are generally where the faultis discriminated from the signal without necessarily considering theclinical context, but where responsive processing is based on the faultand the clinical context information (Regimes I and II). As noted above,however, both fault discrimination and responsive processing may bebased on clinical context information, i.e., the signal and clinicalcontext may both be taken into account in discriminating the fault, aswell as in determining how to respond to the fault (Regime III).

Particular examples would include combinations of the above. In oneparticular example, a fault may be discriminated as due to compressionbased on the clinical context of the time of day, i.e., nighttime.Responsive processing may be based on another clinical context, e.g.,the glycemic state. For example, if the user has a high glucose level,the fault may be compensated for by a prediction.

In another example, a fault may be discriminated as an early woundresponse, i.e., a dip-and-recover fault. The responsive processing maybe to ignore calibrations during this time and revert to establishedfactory values, i.e., a priori calibrations. A calibration may berequested and employed as soon as the dip-and-recover artifact isdetermined to be over.

In yet another example, a water spike or water ingress fault may bediscriminated based on data and clinical context. Responsive processingfor the same may be via a step of compensation, e.g., by subtracting the“spike” profile when presented with contextual evidence, and furtheroptionally performing additional calibration.

In yet another example, if a short duration noise event fault isencountered, and if the glucose rate of change is known and is low,responsive processing may include using a predictive algorithm toestimate the glucose value during the noise event. Further responsiveprocessing may include providing an indicator of the confidence level ofthe signal, e.g., numerically, or using colors such as red, yellow, andgreen, or the like.

Examples

Various specific examples are now provided.

FIG. 24 shows an exemplary occurrence of a compression fault.Compression typically occurs over shorter periods of time, e.g., fromapproximately 20 minutes up to a few hours. In many cases, compressionfaults also happen when glucose levels are relatively stable, becausetypically a user is sleeping and not ingesting food or bolusing insulin.Thus, the beginning of a compression episode may be detected based on adrop in glucose, as compared to predicted values or by examining therate of change. Thus, signal analysis would indicate a drop in potentialor counts, and the clinical context would indicate a difference from anormal glucose profile (for a particular host), difference from apredicted value for the host (based on extrapolation from a real timevalue), or the like. Other clinical context data that may be employedinclude time of day, e.g., nighttime. Further clinical context data maybe that the glucose level was stable prior to the sudden drop.

Responsive processing for the fault, e.g., compensation, may be byprediction, e.g., extending the value of the signal using known ortrusted values, e.g., from when glucose was still reliable, up to someperiod of time, e.g., 40 minutes, so long as the glucose level beforethe episode was higher than some threshold, e.g., 100 mg/dL, and theprevious rate of change was small, e.g., less than 0.5 mg/dL/min

If these conditions are not met, then alternative responsive processingmay be performed. For example, the display may be blanked and the userwoken with the alarm, because if the conditions are not met, the usermay potentially be entering a hypoglycemic state.

Other responses to compression will also be understood. For example, theuser may be prompted to change body positions so as to remove thecompression. However, if the clinical context indicates that the time ofday is night, such prompting may be suspended and responsive processinglimited to actions in a closed loop mode (unless requiring userintervention or alerting). In certain other clinical contexts, theresponsive processing may be to do nothing, in particular if theresponsive processing would add little of value. For example, warning auser when a nighttime compression episode is detected may provide noadditional insight to the user, if their current reading is 180 mg/dL(indicating that the true glucose is above that value). This readingindicates an elevated glucose value, so the clinical response would bethe same, e.g., compensation. Put another way, just because a fault isdetected does not mean that the responsive processing is always anaffirmative action with respect to the fault-the responsive processingmay mean to perform no actions or steps.

As another example, the user's actual glucose level may be 87 mg/dL, andthe CGM may read 77 mg/dL. The fault discrimination algorithm mayproperly detect a compression event based on the signal data andclinical context. The fault discrimination algorithm may quantify thefault as a −25 mg/dL bias, but in this example the true compression biasis actually 10 mg/dL. If the responsive processing is to compensate forthe detected fault, then 25 mg/dL would be added to the CGM reading,resulting in a reading of 102 mg/dL. The alternative is to leave the CGMwith the negative bias. In this case, leaving the CGM with a negativebias is the safer or more conservative approach, and thus the faultdiscrimination algorithm may choose to not perform the step ofcompensation in the circumstance based on the user's glycemic state(e.g., below a predetermined glucose threshold).

With regard to compression, generally multiple inputs feed into theunambiguous determination of a particular fault. As described above withrespect to sensor end of life (“EOL”) determination, methodologies maybe employed to unambiguously determine such faults, or to determine suchwith a desired degree of probability. The multiple inputs may constituterisk factors, and the risk factors can be evaluated periodically orintermittently, e.g., with the receipt of sensor data, or otherwise. Therisk factors can be iteratively determined, averaged, or trended overtime and the results used in later processing.

Suitable risk factors for compression may include sensor reading, sensorvariability, time of day, pattern data, as well as various others. Insome embodiments, the processor module is configured to evaluate thevarious risk factors to provide compression risk factor values, whichmay include simple binary (yes/no) indicators, likelihood or probabilityscores (e.g., relatively scaled or percentages) and/or actual numbers(e.g., outputs of the various tests). As with EOL risk factors, theprocessor module may be configured to run probability functions todetermine a probability of compression and/or a likelihood of recoveryfor one or more of the plurality of compression risk factors. In someembodiments, risk factors are mapped to a score (e.g., from 0 to 1)based on one or more parameters, which then in turn may be mapped byfunctions, which translate a particular risk factor or set of riskfactors to a compression risk factor value, indicating for example, apossibility of the sensor to recover from a particular risk factor fromcompression. Other methods of translating risk factor outputs may beused as is appreciated by a skilled artisan, such as by using one ormore criteria, algorithms, functions or equations. In otherimplementations, fuzzy logic may be employed in the determination of aprobability of a compression fault, as may decision fusion, both ofwhich are described elsewhere. Look up tables, expert rules, neuralnets, and the like may also be employed in the determination accordingto implementation.

In the above example multiple alternatives were seen for responsiveprocessing. For certain faults, there may be only one alternative. Forexample, if the fault is dip-and-recover or oxygen noise, the displaymay be blanked regardless of other contextual information or specificcharacteristics of the data.

FIG. 25 depicts the case of an early wound response, e.g., “adip-and-recover” fault. Such faults tend to appear in many ways like lowglucose levels, and it is sometimes difficult to discriminate the sameby just reviewing the uncalibrated data without consideration of theclinical context.

As noted above, dip-and-recover faults are characteristic of recentlyimplanted sensors due to physiological early wound responses. Thus, inone exemplary implementation, and referring to the flowchart 344 of FIG.26, the time since implant may be used as a signal analysis criterion infault discrimination. For example, if signal analysis indicates that thetime since implant is between, e.g., two and six hours (step 346), andif the clinical context is determined to be that a hypoglycemic state isentered (step 348), then a potential fault may be detected (step 351).

To discriminate the fault, one type of responsive processing is to entera frequent sampling mode (step 352), e.g., every 30 seconds, in order toascertain the rate of change of the glucose level. If the rate of changeis characteristic of a dip-and-recover fault (step 354), e.g., the signis negative and the magnitude is greater than a threshold, then varioustypes of responsive processing may take place. For example, the usercould be prompted to measure their blood glucose level manually, e.g.,via a finger stick (step 356). Alternatively, where an appropriatesensor has been provided, another different chemical species, e.g., NO,may be measured that may be released by inflammatory cells that arebelieved to be caused by the dip-and-recover fault, e.g., because thesame may consume the glucose. In some cases, both steps may beperformed. In this way, the fault would be discriminated both on thedata and/or on the clinical context.

If the fault is discriminated as due to dip-and-recover, then responsiveprocessing may occur. The responsive processing may take a number offorms, including compensating for the fault by depending on thepatient's last blood glucose entry (step 362) for a prediction orforecasting. In some cases, if the underlying signal is notrepresentative of the glucose concentration and if predictive algorithmsare not usable, e.g., because of minimal data, then the compensationstep may be skipped and no action performed (step 364).

Other types of responsive processing will also be understood. Forexample, if the blood glucose was previously measured in a hyperglycemicrange, than the display screen of the monitor device may be blanked(step 366), so as to not convey a potentially erroneous reading. As thepatient started in a hyperglycemic state, but the rate of changeindicated a decrease in glucose value, such may not immediately presenta dangerous situation. Of course, the length of time for which thedisplay screen is blanked may vary depending on the clinical context,e.g., level of the hyperglycemia, magnitude of negative rate of change,and the like.

On the other hand, if the patient started off euglycemic orhypoglycemic, then the patient may be alerted (step 368). In this case,just in case the rate of change is reflecting the actual glucose value,and is not caused by a dip-and-recover fault, then the alert may bethrown to warn the patient of a potential impending hypoglycemic state.As with the hyperglycemic state, the actual steps taken may depend onother aspects of the clinical context.

Certain implementations may call for querying the patient (step 372), inorder to obtain additional information about the clinical context. Forexample, the patient may be queried as to whether they ingested a mealin the last few hours, and/or recently administered insulin. If nopatient response ensues, an alarm may be sounded.

Other variations include providing modifiers to the displayed glucosevalue, e.g., a range of glucose values, to indicate potential clinicalvalues due to the uncertainty caused by the fault. Historical data mayalso be employed, e.g., based on the time of day and other clinicalcontexts, to calculate a range or to inform other responsive processing.

As with compression faults and EOL determination, dip and recover faultsalso generally involve feeding multiple inputs into their determination.And as above, methodologies may be employed to unambiguously determinesuch faults, or to determine such with a desired degree of probability,including the consideration of multiple risk factors evaluatedperiodically or intermittently.

Suitable risk factors for dip and recover may include sensor reading,time since implant, pattern data, as well as various others. In someembodiments, the processor module is configured to evaluate the variousrisk factors to provide dip and recover risk factor values, which mayinclude simple binary (yes/no) indicators, likelihood or probabilityscores (e.g., relatively scaled or percentages) and/or actual numbers(e.g., outputs of the various tests). As with EOL risk factors,probability functions may be run by the processor module to determine aprobability of dip and recover and/or a likelihood of recovery for oneor more of the plurality of risk factors. Other methods of translatingrisk factor outputs may be used as is appreciated by a skilled artisan,such as by using one or more criteria, algorithms, functions orequations. In other implementations, fuzzy logic may be employed in thedetermination of a probability of a dip and recover fault, as maydecision fusion, both of which are described elsewhere. Look up tables,expert rules, neural nets, and the like may also be employed in thedetermination according to implementation.

FIG. 27 illustrates fault discrimination of a “shower spike” based onsignal analysis including temperature data and time of day criteria,which when combined provide clinical context information indicative of apatient showering. In particular, in a signal analysis step, the sensorsignal output 374 indicates a rise in signal at point 375, whichcorrelates with a rise in temperature at point 377 in the temperatureplot 376. In analysis of the clinical context information, the time ofday of the spike is consistent with the time of a user's shower, eitherin comparison to other users or based on pattern data for thisparticular user. Other clinical context information may be seen, e.g., adrop in temperature, at portions 382 and 384, prior to the spike atpoint 377, which may indicate the patient has gotten out of bed.

To further discriminate this fault, having identified a potential faultbased on signal analysis and clinical context, testing may be performedto look for “short circuited” electrodes. For example, a self-diagnosticmode may be entered and the bias potential changed. The system may thenlook for an absence of a response (short-circuits may generally be seento be non-responsive to a various given stimuli).

For example, in one implementation, systems and methods according topresent principles may provide a method of discriminating a fault,including a step of identifying a potential fault based on signalanalysis and data about clinical context. Other steps may includeentering a self diagnostics mode and performing various tasks, e.g.,changing the bias potential and examining a response. For example, theabsence of a response may indicate a “short circuit”, as the same maygenerally be seen to be nonresponsive to a various given stimuli.

As with EOL, compression, and dip and recover faults, suitable andmultiple risk factor inputs may be employed in the determination of ashower spike fault, using statistical and probabilistic models,including fuzzy logic and decision fusion analyses, as well as usinglookup tables or the like in the determination.

FIG. 28 illustrates another example of fault discrimination of acompression fault. Trace 386 corresponds to temperature, and traces 388and 392 correspond to unscaled paired sensor traces. The signal analysischaracteristics based on the traces include low levels of high-frequencynoise 394, as well as abrupt shifts 396 in sensor signal at thebeginning and end of compression events. These shifts are illustrated inthe sensor trace 388. The paired sensor trace 392 represents a similartype of sensor, worn on the other side of the patient, and thus notsubject to compression. The trace 392 accordingly shows a reliableglucose signal compared to the trace 388 having significant artifacts.Clinical context information indicates a sleeping user, which may bedetermined by the time of day compared to certain criteria for sleeping.Other clinical context information includes elevated temperatures, aswell as a lack of meter values (not shown), indicating the patient hasnot recently taken a finger stick.

In one implementation of a method for fault discrimination of acompression fault, a signal is received and analyzed for variousaspects. For example, the received signal may be analyzed for low levelsof high-frequency noise. As another example, the received signal may beanalyzed for shifts in sensor signal, greater than a predeterminedthreshold, at the beginning and end of a significant or sustaineddecrease in sensor signal, e.g., one characterized by a steep decline insignal value, followed by a period of sustained decreased value,followed by a steep increase in the signal value. The method for faultdiscrimination may further include analysis of clinical context datacompared to clinical context criteria in order to determine clinicalcontext information. For example, the received clinical context data mayinclude an elevated temperature compared to that which may be expectedin the absence of the fault, the time of day, e.g., if it is expectedtime for sleeping, as well as other such data. If two sensors are worn,the received signals may be analyzed for situations where once sensorsees a decrease in signal value and the other does not. According to theabove noted signal analysis and the clinical context information, thesystem and method may discriminate that a compression fault hasoccurred.

FIGS. 29A and 29B illustrate another example of fault discrimination,with the fault again being water ingress. These figures represent thesame patient on different days. Traces 402 and 402′ indicate temperaturereadings, and traces 404 and 404′ indicate sensor readings.

The clinical context information may be determined in a number of ways,e.g., by comparing the temperature against the clinical context criteriaof an expected temperature, by comparing the time of day (or anotherscale, e.g., time of week), against clinical context criteria, or thelike, and in this way determining behavior patterns, e.g., showering.Such patterns may be seen to be highly consistent on weekdays, and thusthe clinical context information in this example indicates a showeringuser. More particularly, the clinical context criteria indicates aregular time of day at which the signal experiences an abrupt increase(see the noted fault region), followed by a decay over a multiple hourperiod. Other data which may be compared to clinical context criteria todetermine clinical context information includes temperature, e.g., adecrease in temperature, likely caused by the user rising from bed, aswell as noise, e.g., a noise level in preceding data, such as may becaused by water ingress caused by a shower.

In this case, temperature compensation would be insufficient tocompensate for the shower spike. In particular, while some prior effortsat performing temperature compensation have used measurements oftemperature in vivo, at the sensor site, and ex vivo, on thetransmitter, in the case of water ingress the problem is not caused byan incorrect or inapplicable temperature reading at the sensor; rather,the same is caused by a short circuit 29 to water ingress into thetransmitter. In fact, the 27 of the temperature sensor in FIG. 30 isopposite to that of the temperature sensor in FIG. 28, though both arecaused by water ingress. Thus, providing a level of temperaturecompensation without further signal analysis and clinical context, e.g.,by adding a constant value, can lead to significant errors. Accordingly,temperature used as an input here should be understood to be applied inthe context of comparing temperature data to predetermined clinicalcontext criteria to determine clinical context information (e.g.,whether a user is sleeping, showering, or the like).

In more detail, water ingress faults cause moisture to enter the seal orenter cracks in the insulator, in either case instigating additionalsignals that are not related to glucose, though the signals stillemanate from an electrochemical mechanism (though different from that ofglucose). The signal from the non-glucose related mechanism is afunction of various factors, including the additional exposed surfacearea of the sensor, the reaction with the non-glucose analyte, and theexposure of different working electrodes to moisture. Duringamperometric detection, the signals from both sources look similar andare difficult to distinguish. However, in some cases a unique signaturecan be obtained from an actual electrochemical reaction with theanalyte. The electrochemical signal coming from exposure of additionalsurface area also differs from that of other interferants, e.g.,acetaminophen.

Thus, in one implementation, electrochemical means can be used to obtaina quantitative measure of the surface area using multiple potentials orAC voltammetry or pulsed voltammetry, thus giving another indication ofwater ingress.

For example, AC voltammetry may be intermittently performed to share thefunction of the working electrode, e.g., glucose detection may occur forfour minutes out of a five-minute cycle, while for the last-minute, anoscillating potential can be applied to the electrodes to see if any ofthe signals are from nonglucose related signals, or those related (ornot) to hydrogen peroxide or other potentially interfering analytes.Distinguishing or separating interfering analytes from each other is notnecessary, just distinguishing moisture ingress signals from othersignals is generally required in fault discrimination of this type. Theabove signal apportionment is just an example. In general, this methoduses a portion of the measurement cycle for error checking in to see ifthere is any other unexpected electroactive surface area exposure. Othertechniques that may be employed for such include oscillating potentials,impedance measurements, pulsed amperometric detection, and the like.

For example, in one implementation, systems and methods according topresent principles may be employed to measure or discriminate a wateringress fault by use of the following steps. In a first step, a signalis received, the signal pertaining to an electrochemical mechanismcaused by an analyte and a sensor. In a next step, a quantitativemeasure of the surface area is determined, e.g., from the signal or fromalternate electrochemical means, e.g., multiple potentials, ACvoltammetry, pulsed voltammetry, or the like. The quantitative measureof the surface area is then employed to determine if water ingress hasoccurred to see, e.g., if a portion of the surface area of the sensor isdeleteriously taken up by moisture. In some cases, additional steps maybe performed, such as detecting a signature is detected from the signal,the signature associated with an interferant and/or with a level ofsurface area of the sensor.

FIG. 30 illustrates an example of signals in which the fault of“end-of-life noise” can be discriminated on sensors worn simultaneouslyon a patient. The units for the sensor output, upon scaling, are current[nano-amps]/clinical glucose value [mg/dL] or nano-A/mg/dL. Traces 408and 412 are shown, where trace 408 is the sensor trace illustrating thefault. The trace 412 illustrates a reliable signal, while the trace 408has been rendered unreliable because of the fault. As noise can be sitespecific, e.g., influenced by the wounding of the particularmicroenvironment, it is not surprising to see a site-specific faultoccur in one location on the patient but not another location on thepatient worn over the same time period.

Certain characteristic shapes 414 for trace 408 can be seen and used todiscriminate the fault, including an abrupt downward spike at thebeginning of a noise episode, high-frequency noise present throughoutthe episode, and a positive overshoot at the end of the noise episode.Signal analysis may also show other potential signal criteria, includingthat noise episodes tend to be proximate in time to similar episodes,and the tendency for the episodes to become more frequent as time goeson and the sensor endures more wear. Another signal-relatedpredetermined criterion which may be used to discriminate this type offault is that the fault generally coincides with a gradual decrease insensitivity. One type of clinical context information for this faultincludes that the fault more frequently occurs when glucose is elevated.Another type of clinical context information criterion is that there isan increased probability of occurrence of the fault if there exists ahigh average sensor current during the session, or a high integratedcurrent from the start of the session. Other exemplary parameters thatmay be employed in end-of-life detection include amplitude and/orvariability of sensitivity, e.g., generally indicating a decline of 5%,10%, 20%, over the last 6, 8, 10, 12, 24 hours, as well as noisepatterns, spectral content, days since implant, oxygen concentration, aglucose value, an error in glucose value at calibration, or the like.

In a particular implementation of systems and methods according topresent principles, in particular applied to the discrimination of thefault of end-of-life noise, steps may include receiving a signal tracein analyzing the signal trace for certain characteristic shapes. Forexample, the signal trace may be analyzed to detect an abrupt downwardspike at the beginning of a noise episode, high-frequency noise presentduring the noise episode, and a positive overshoot at the end of thenoise episode. If such is seen, at least an initial determination ordiscrimination of end-of-life noise may be made. Other aspects maycontribute to such a determination or discrimination. For example, ifmultiple such signal traces are seen, especially over a predeterminedtime window, where each signal trace includes the above aspects, thelikelihood or probability of end of life noise may be increased, and theconfidence level of such a determination or discrimination may be causedto rise. If such episodes become more frequent as time goes on, againthe likelihood or probability of end of life noise may be increased, andthe confidence level of such a determination or discrimination may becaused to rise. In the same way, if additional data is detected aboutthe sensitivity of the sensor, and if the sensitivity is seen todecrease over time, particularly in a gradual way, then again thelikelihood or probability of end of life noise may be increased, and theconfidence level of such a determination or discrimination may be causedto rise.

Clinical context information may also cause the likelihood orprobability of end of life noise to be increased, and thus so too theconfidence level of such a determination or discrimination. For example,if the glucose value has been elevated for a long period of time, suchmay tend the increase the likelihood or confidence of the determinationof an end-of-life fault. Other types of clinical context informationthat serve as an input into the determination or discrimination of anend-of-life fault include: time since implant, oxygen concentration,glucose values, errors at calibration, or the like.

FIG. 31 illustrates another example of a dip-and-recover fault. In thisexample, the user wore two sensors simultaneously, both of which showedsome artifact, but one which showed a more severe fault, caused by a dipand recover fault. In particular, the trace 416 is a sensor traceshowing a dip and recover fault, while trace 418 only shows artifactsrelated to noise. The circles 422 represent meter values.

As may be seen at point 424, one signal characteristic indicative of adip-and-recover fault includes a signal drop that is inconsistent withthe meter values 422. Another potential signal characteristic is anincrease in noise in a specific frequency range (seen in both traces 416and 418), or in noise that does not correlate with paired redundantsensor (note lack of correlation between 416 and 418 during dip andrecover). The level of noise in a specific frequency range can bedetermined by an appropriate frequency transform. A further potentialsignal characteristic consistent with a dip-and-recover fault is adownward deviation of the signal from the redundant sensor data, whichis also show in FIG. 31 by the deviation between trace 418 and trace416. One type of clinical context information that may be employed infault discrimination or responsive processing includes time sinceimplantation, as the onset of this type of fault generally occursseveral hours after sensor insertion.

Accordingly, in one implementation, systems and methods according topresent principles are directed to ways to discriminate dip and recoverfaults. A first step in an exemplary method is to receive a signal andto analyze the received signal. Various characteristics can be employedin the analysis to determine if the received signal is consistent with adip and recover fault. For example, if the received signal decreases atthe same time as blood glucose meter values do not decrease, adetermination or discrimination of a dip and recover fault may be made.Alternatively, if an increase in noise in a specific frequency range isseen, such may also lead to a determination or discrimination of a dipand recover fault. If the sensor is paired, i.e., a user is wearing twosensors, noise in one but not in the other, or a signal decrease in onebut not in the other, may further lead to a determination ordiscrimination of a dip and recover fault. In the method of adetermination or discrimination of a dip and recover fault, clinicalcontext information may also be employed. For example, clinical contextdata may be received by systems or methods according to currentprinciples, where the clinical context data constitutes time sinceimplantation, and the same may be compared against criteria, e.g.,wherein the criteria includes if the time since implantation is beforeor after a predetermined threshold amount of time from implantation,e.g., 12 hours. If the signal information shows a decrease compared to ablood glucose meter values, or exhibits an increase in noise in aspecific frequency range, or meets one of the other criteria notedabove, and the time since implantation is less than the predeterminedthreshold, then the determination or discrimination may indicate theoccurrence of a dip and recover fault.

FIG. 32 illustrates another type of fault, i.e., lag. Results are shownfor two different sensors implanted in a host simultaneously,illustrated by traces 428 and 432, with corresponding peak detectedcurves 432 and 434, respectively. Once sensor (traces 426 and 434)experienced a few minutes of lag compared to the other. Such lag errorsmay be important in the context of falling glucose after a meal, withthe risk being that a low glucose alarm might be delayed or missed. Thisphenomenon might be a permanent characteristic of the sensor site or itmay be transient, depending on local blood perfusion. In any case,responsive processing may be performed, and in particular the use of apredicted or forecasted value, based on glucose concentration and/orrate of change. In this way the effect of the time lag may be mitigated,so that the same does not cause the user to delay responding to ahypoglycemic event.

In a particular implementation of systems and methods according topresent principles, the same may be employed for the discrimination ofsuch lag faults. A first step is to receive the signal from a monitor,e.g., a CGM or other analyte monitor. A next step is to analyze thesignal for the presence of lag. The analysis for lag may includeanalyzing the received data signal itself or analyzing the receivedsignal along with another received signal, e.g., one from a pairedglucose sensor. Once the fault of lag is determined or discriminated,responsive processing may be performed. For example, for lags greaterthan a predetermined threshold, or indeed for any lags, a predicted orforecasted value may be displayed to the user instead of the laggedvalue, to provide a more accurate indication to the user of theircurrent situation.

FIGS. 33A-33D illustrate another example of the fault of compression, inthis case as evidenced in pediatric patients. A raw signal is shown,measuring counts, where generally 200,000 counts corresponds to aclinical glucose value of 100 mg/dL. FIGS. 33A and 33C show multi-daydata for two different patients, while FIGS. 33B and 33D illustrate moredetailed views of a particular compression episode within each of FIGS.33A and 33C, respectively. As may be seen, the sensor signal dropscompletely to a baseline value during these compression faults. In thesecases, the sensor was worn on the lower back/buttocks. FIGS. 33A and 33Bfurther illustrate a rebound effect after compression, where, followingrelief of the compression, the signal overshoots the equilibrium orprior raw signal value.

In another implementation, faults may be detected by identifying asignal shape with a known signal shape that pertains to a fault. Inparticular, when a signal under evaluation consists of one or morepredictable shapes, it is beneficial to establish an expectation ofnormal or abnormal signal characteristics, in order to detect artifactsand aberrations. Such an expectation, or a “template”, can be comparedto every newly arriving signal to assess its correlation to or deviationfrom the template. This comparison can be made to detect failure modeswith characteristic impacts on the sensor signals, e.g., shapes, ordamped or unstable responses, in order to discriminate between knownfault modes, as well as to assess their severity.

In such systems, one way to achieve accurate blood glucose readings isto identify blood draws with pressure and glucose sensor signals thatare consistent with patient blood access and typical enzyme sensorresponses. A goal in the process is to discriminate between faultyconditions that the monitoring algorithm can reliably mitigate andfaulty conditions that produce glucose measurements that do not meetrequired accuracy. When the algorithm cannot display accurate results,the decision logic may classify failure modes with known mechanisms andcharacteristics into actionable alerts. These alerts may identify faultsthat require user action to resolve, or faults indicating completesensor failures.

Referring to the flowchart 431 of FIG. 34A, two steps may be seen in theprocess. A first step is the generation of templates for signals in themeasurement cycle (step 433). A second step is the matching of thetemplates to the received data (step 435). The steps are now describedin greater detail.

In the generation of templates, one approach uses singular valuedecomposition or a related factor analysis method to determine thesources of variation in a training set. To do this, a training set iscompiled using a representative data set for reliable operation thatmeets the accuracy requirement or that targets a known failure mode.Such a set is arranged in an m×n matrix M, of sensor signals versustime, where m is the number of samples, stored as row vectors, and n isthe number of time points in each sample. The signals can be from anelectrochemical sensor, e.g., transient signal analysis from a steadystate or transient measurement system, which may gain particular benefitfrom fast sampling of the data, as described in more detail elsewhereherein.

A singular value decomposition is performed using an availablesubroutine, e.g., Matlab®'s SVD function: M=USV^(i). V is an n×n matrixthat contains the singular vectors in order of decreasing contributionto the overall signal. In other words, the first column of V willinclude the feature that is most prominent in the training set, thesecond column will include the next most prominent feature, and so on.In one approach, the most prominent feature, i.e., the first singularvector, is converted into a signal template. In another approach, asignal template is a linear combination of singular vectors. Otherapproaches will also be understood.

Yet another approach uses a physical or mathematical model of the systemto generate templates for the sensor response. An example would be amathematical model for sensor response based on compression artifacts.Such models may be employed to generate the dynamic response seen intypical compression artifacts. Another example would be a mathematicalmodel for sensor response based on diffusion rates. Such models may beemployed to generate the dynamic response for a reliable sensor or togenerate the dynamic response for a sensor that was slowed by biologicalfouling or encapsulation. Other mathematical models may be generated forother such signals derived from, for example, step or cyclic voltagecycles (AC or DC), intermittent exposure to a sample, or the like.

In the second step, i.e., matching template to data, the sensor signalscan be the sensor response versus time or may be preprocessed to filterout electronic noise or other data collection artifacts. Each sample ofincoming data is then projected onto one or more templates to determineits correlation to (or deviation from) the template in order to detectparticular features and failure modes. The result of the projectiongives a contribution of that particular template shape to the overallshape of the sensor signal.

In another implementation of the second step of matching template todata, the expected sensor response may be shifted in time to compensatefor acceptable manufacturing, operational, and physiological variationsthat change fluid volumes. For example, time shifts may result fromchanges in catheter volume or sensor position that affect dead volume.The shifted sensor response can then be matched against templates.

Yet another approach allows for the sensor response to be stretched orcompressed in time to again compensate for acceptable manufacturing,operational, and physiological variations that may arise. For example,such signal variations may result from changes in peristaltic pumpefficiency or sensor response changes with temperature. An example ofthe method of FIG. 35A is described below.

Referring to FIG. 34B, a signal schematically illustrating a compressionartifact is shown. Typical aspects include a pre-compression “regular”signal portion 411, a post-compression “regular” signal portion 413, asteep downward slope 415, a steep upward slope 439, and a flat sectionbetween the slopes 437. The downward slope generally indicates theoccurrence of the compression, and the upward slope indicates relief ofthe compression. The time between the two may vary, but is generally afew minutes to a few tens of minutes.

Compression artifacts generally have a shape such as illustrated, andthus a template may accordingly be generated and the same used ascriteria against which incoming signals are evaluated. For example, andreferring to FIG. 34C, an exemplary signal template 449 is illustratedhaving horizontal bands 411′ and 413′, a downward slope band 415′, andan upward slope band 439′. A flat portion band 437′ is also illustrated,and it will be understood that the length of this band (in time) mayvary depending on how long the compression occurs. So long as theincoming signal is within the bands, i.e., so long as the data fits theclinical context criteria, a compression fault, i.e., clinical contextinformation, may be determined. For example, a number of slopes fordownward and upward signal waveforms 441 and 443 respectively areillustrated, and such are still within the clinical context criteria asset by the bands. On the other hand, a signal slope 447 is illustratedon the downward side, and a signal slope 447′ is illustrated on theupward side, that do not fit within the bands and would thus not meetthe clinical context criteria for a compression fault.

It will be understood that numerous variations may occur. For example,the position of the bands 411′ and 413′ within the template 449 may varysignificantly in their vertical (signal value) position. The width ofthe bands 411′ and 413′ may be larger than the width of the band 437′,or may be the same. Other variations will also be understood, as well asways of providing templates without using such bands, for example, othermathematical models such as correlation analysis to a curve (template),or the like.

To determine the template, the SVD routine may be run over a largetraining set of individual compression artifacts collected from a widevariety of different sensor hosts whom experienced the compressionartifact. The known compression artifact signature provides a toolagainst which each possible compression artifact may be evaluated.Multiple such templates may be created, and each time a compressionartifact is detected, the measured signal may be projected onto each ofthe templates to obtain their contributions to the overall shape. Whilecompression artifacts are exemplified herein, the same principles ofcreating and using templates for comparison against any known signature(e.g., EOL, dip and recover, transient signals obtained during aself-diagnostics cycle, or any other waveform that is produced by thesensor by any known methodology) may be applied, as is appreciated byone skilled in the art.

FIGS. 35A-35C illustrate a number of examples of signals which may becompared against templates. FIG. 35A illustrates an exemplarycompression artifact. FIG. 35B illustrates an artifact that may becompared to the template. In this plot, the overall shape is somewhatconsistent with a compression artifact, but with additional noise, butthe same can still be quantified as yes/no and/or determined in terms ofa confidence factor. FIG. 35C illustrates some other type of signalartifact, other than compression. The signal is not well explained byeither the typical compression waveform or the normal glucose behavior,although the signal correlates more closely with the normal glucosebehavior. Accordingly, while the compression artifact may not bediscriminated in the particular scenario of FIG. 35C, a prompt could besent to the user to provide additional information and/or otherprocessing applied.

Thus, using the templates generated from a training set allows thealgorithm to detect a particular failure mode that manifests itself as aparticular waveform. Given a sufficiently large training data set, moretemplates can be easily generated for other failure modes that requirediscrimination. The results from template matching can be combined withclinical context information to discriminate failure modes and thusdiscriminate faults.

Generally the templates are created over large data sets from differentpatients in an empirical sense, although in certain implementationsother ways of establishing templates may also be employed, includingusing templates established from a single patient.

What has been disclosed are systems and methods for dynamically anditeratively providing fault discrimination and responsive processing. Avariety of methods have been disclosed for performing faultdiscrimination, as well as for processing subsequent to faultdiscrimination, including remedial measures.

Variations will be understood to one of ordinary skill in the art giventhis teaching. For example, while certain clinical context have beendescribed above, where clinical context data is compared againstclinical context criteria to develop clinical context information, itwill be understood that the above-noted clinical contexts are exemplaryand do not constitute an exhaustive list. For example, sensor insertionsite may also serve as a clinical context. Certain sensor insertionsites may lead to a greater occurrence of fault such as dip and recover,water ingress, compression, or the like, and thus by consideration ofsuch contexts, the discrimination or determination of a fault can bemade with greater accuracy. In another variation, while in vivo sensorsand measurements are generally described above, in some implementationsex vivo sensors and measurements may also be employed. In yet anothervariation, while continuous measurements are generally described above,certain implementations may take advantage of periodic or intermittentmeasurements. Other variations and types of clinical contexts will alsobe understood.

As yet another example of variations, techniques have been described fordiscriminating and responding to compression faults. Compression faultsmay cause CGM devices to become inaccurate when the tissue surroundingthe sensor is compressed. It is believed that the compression of thetissue causes the reduced perfusion of glucose to and/or oxygen aroundthe sensor (and resulting compressed signal). The effect typicallyoccurs for short periods of time, such as 5 or 20 minutes to 60 minutesup to several hours. The accuracy returns when the patient adjustspositions and no longer compresses the sensor. In addition to (oralternative to) the other methods for detecting compression artifacts, acompression sensor can be placed in the transmitter or disposablesensor. The compression sensor can indicate directly if the tissue isbeing compressed in the region. If activated, several actions can betaken, e.g., an alarm can sound, data can be blanked by the receiver, orthe patient may be alerted via a small shock, vibration, or the like. Ifthe system is hooked up to a pump, a specific action or inaction can betaken, such as suspending insulin. In addition, the sensor can bedesigned so as to give the patient discomfort if the patient iscompressing the sensor, discouraging lying on the sensor.

For example, referring to FIG. 36, a transmitter with integrated forcesensor 436 is illustrated. In this implementation, a miniature pressuretransducer is disposed immediately under the sensor transmitter. Inparticular, a transmitter 436 formed by combining two parts, a rigidbase 444 carrying the printed circuit board and a rigid cover 437. Acompressible gasket 454 is provided allowing the cover to move to andfrom the base depending on externally applied forces. On the printedcircuit board, a pressure sensing element 442 is provided which iscoupled to the cover 437 by, e.g., a contacting pin 438. If force isapplied to the transmitter, the cover is pushed downwards and a pressurecan be sensed using the pressure sensor. In an alternative embodiment,the compressible gasket is omitted, and the cover may be provided inthis case with a thin flexible section which deflects upon theapplication of force.

The pressure transducer measurements may be used to assistidentification of spurious hypoglycemic values associated withcompression applied directly to the sensor and transmitter pad.Exemplary pressure transducers include those using miniaturepiezoelectric pressure transducers, strain gauges, springs, capacitancemeasurements, and the like. Spuriously low glycemic measurementsassociated with compression would not as a consequence result in alarmsor in other uncalled-for therapeutic action. A special algorithm couldcombine the pressure transducer data with the previous 60 to 90 minutesglucose trend data to further assist in differentiating actualhypoglycemic events from spurious readings induced by compression at thesite of the transmitter and sensor. In this way, the phenomenon of“alarm fatigue” is minimized, increasing the likelihood that a user willrespond to other alerts.

In addition, CGM systems may be employed as part of an automated insulininfusion system or artificial pancreas system. Such systems wouldgenerally include automatic suspension of insulin infusion in responseto detected actual or impending hypoglycemia. As above, if the detectionof hypoglycemia is correct, such an insulin pump suspension iswarranted. However, if the hypoglycemia detected by the sensors iserroneous, there is the risk that an automatic pump suspension couldlead to severe hyperglycemia, possibly culminating in diabeticketoacidosis. Using the system of FIG. 36, an independent method may beemployed of determining whether sensor readings are anomalous by usingdata from a real-time pressure transducer, significantly improvingaccuracy of readings and thus treatment to a patient.

In another variation, while various types of sophisticated responsiveprocessing techniques have been disclosed, another way to handle faultsor failures is to notify the patient of the problem, and to configurethe system to enter a failsafe mode or to shut the sensor off.

In yet another variation, in implementations above in which a predictedor forecasted value is suggested, any method of forecasting orprediction using historic and current data values may be applied,including methods relating to pattern analysis, use of clinical context,and the like. However, a simple linear regression may also be applied.In this instance, a certain amount of data is used in a linearregression, and the same used to calculate a latest value using theregression-determined line. For example, data may be taken every 30seconds over a five-minute period, and the same may be used in theregression analysis. This technique may also serve to smooth the dataand to remove the time lag. Residuals around the line may be used as anestimate of noise level. In enhanced techniques, limits may be placed onthe slope of the line computed, so as to reflect proper physiologicallimits. Limits may also be placed on how much the slope of the line canchange between each five-minute interval. In a particularimplementation, a linear regression is taken over 10 samples, and apredicted value is computed for the endpoint of the line, reducing theamount of noise and filter time delay significantly.

This idea is illustrated in FIG. 37, in which points 456 delineatebeginnings and endings of different 5 minutes sampling periods. 10samples are taken in each five-minute period, corresponding to 30 secondintervals. Using linear regression, the estimated glucose value for theendpoint of the line is calculated in a particularly rapid fashion. Thisprovides a more rapid or adaptive method for performing responsiveprocessing.

The connections between the elements shown in the figures illustrateexemplary communication paths. Additional communication paths, eitherdirect or via an intermediary, may be included to further facilitate theexchange of information between the elements. The communication pathsmay be bi-directional communication paths allowing the elements toexchange information.

The various operations of methods described above may be performed byany suitable means capable of performing the operations, such as varioushardware and/or software component(s), circuits, and/or module(s).Generally, any operations illustrated in the figures may be performed bycorresponding functional means capable of performing the operations.

The various illustrative logical blocks, modules and circuits describedin connection with the present disclosure (such as the blocks of FIGS. 2and 4) may be implemented or performed with a general purpose processor,a digital signal processor (DSP), an application specific integratedcircuit (ASIC), a field programmable gate array signal (FPGA) or otherprogrammable logic device (PLD), discrete gate or transistor logic,discrete hardware components or any combination thereof designed toperform the functions described herein. A general purpose processor maybe a microprocessor, but in the alternative, the processor may be anycommercially available processor, controller, microcontroller or statemachine. A processor may also be implemented as a combination ofcomputing devices, e.g., a combination of a DSP and a microprocessor, aplurality of microprocessors, one or more microprocessors in conjunctionwith a DSP core, or any other such configuration.

In one or more aspects, the functions described may be implemented inhardware, software, firmware, or any combination thereof. If implementedin software, the functions may be stored on or transmitted over as oneor more instructions or code on a computer-readable medium.Computer-readable media includes both computer storage media andcommunication media including any medium that facilitates transfer of acomputer program from one place to another. A storage media may be anyavailable media that can be accessed by a computer. By way of example,and not limitation, such computer-readable media can comprise varioustypes of RAM, ROM, CD-ROM or other optical disk storage, magnetic diskstorage or other magnetic storage devices, or any other medium that canbe used to carry or store desired program code in the form ofinstructions or data structures and that can be accessed by a computer.Also, any connection is properly termed a computer-readable medium. Forexample, if the software is transmitted from a website, server, or otherremote source using a coaxial cable, fiber optic cable, twisted pair,digital subscriber line (DSL), or wireless technologies such asinfrared, radio, and microwave, then the coaxial cable, fiber opticcable, twisted pair, DSL, or wireless technologies such as infrared,radio, and microwave are included in the definition of medium. Disk anddisc, as used herein, includes compact disc (CD), laser disc, opticaldisc, digital versatile disc (DVD), floppy disk and Blu-ray® disc wheredisks usually reproduce data magnetically, while discs reproduce dataoptically with lasers. Thus, in some aspects a computer readable mediummay comprise non-transitory computer readable medium (e.g., tangiblemedia). In addition, in some aspects a computer readable medium maycomprise transitory computer readable medium (e.g., a signal).Combinations of the above should also be included within the scope ofcomputer-readable media.

The methods disclosed herein comprise one or more steps or actions forachieving the described methods. The method steps and/or actions may beinterchanged with one another without departing from the scope of theclaims. In other words, unless a specific order of steps or actions isspecified, the order and/or use of specific steps and/or actions may bemodified without departing from the scope of the claims.

Certain aspects may comprise a computer program product for performingthe operations presented herein. For example, such a computer programproduct may comprise a computer readable medium having instructionsstored (and/or encoded) thereon, the instructions being executable byone or more processors to perform the operations described herein. Forcertain aspects, the computer program product may include packagingmaterial.

Software or instructions may also be transmitted over a transmissionmedium. For example, if the software is transmitted from a web site,server, or other remote source using a coaxial cable, fiber optic cable,twisted pair, digital subscriber line (DSL), or wireless technologiessuch as infrared, radio, and microwave, then the coaxial cable, fiberoptic cable, twisted pair, DSL, or wireless technologies such asinfrared, radio, and microwave are included in the definition oftransmission medium.

Further, it should be appreciated that modules and/or other appropriatemeans for performing the methods and techniques described herein can bedownloaded and/or otherwise obtained by a user terminal and/or basestation as applicable. For example, such a device can be coupled to aserver to facilitate the transfer of means for performing the methodsdescribed herein. Alternatively, various methods described herein can beprovided via storage means (e.g., RAM, ROM, a physical storage mediumsuch as a compact disc (CD) or floppy disk, etc.), such that a userterminal and/or base station can obtain the various methods uponcoupling or providing the storage means to the device. Moreover, anyother suitable technique for providing the methods and techniquesdescribed herein to a device can be utilized.

It is to be understood that the claims are not limited to the preciseconfiguration and components illustrated above. Various modifications,changes and variations may be made in the arrangement, operation anddetails of the methods and apparatus described above without departingfrom the scope of the claims.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated. Terms and phrasesused in this application, and variations thereof, especially in theappended claims, unless otherwise expressly stated, should be construedas open ended as opposed to limiting. As examples of the foregoing, theterm ‘including’ should be read to mean ‘including, without limitation,’‘including but not limited to,’ or the like; the term ‘comprising’ asused herein is synonymous with ‘including,’ ‘containing,’ or‘characterized by,’ and is inclusive or open-ended and does not excludeadditional, unrecited elements or method steps; the term ‘having’ shouldbe interpreted as ‘having at least;’ the term ‘includes’ should beinterpreted as ‘includes but is not limited to;’ the term ‘example’ isused to provide exemplary instances of the item in discussion, not anexhaustive or limiting list thereof; adjectives such as ‘known’,‘normal’, ‘standard’, and terms of similar meaning should not beconstrued as limiting the item described to a given time period or to anitem available as of a given time, but instead should be read toencompass known, normal, or standard technologies that may be availableor known now or at any time in the future; and use of terms like‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

Where a range of values is provided, it is understood that the upper andlower limit and each intervening value between the upper and lower limitof the range is encompassed within the embodiments.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention, e.g., as including any combination ofthe listed items, including single members (e.g., “a system having atleast one of A, B, and C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.). In those instanceswhere a convention analogous to “at least one of A, B, or C, etc.” isused, in general such a construction is intended in the sense one havingskill in the art would understand the convention (e.g., “a system havingat least one of A, B, or C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Headings are included herein for reference and to aid in locatingvarious sections. These headings are not intended to limit the scope ofthe concepts described with respect thereto. Such concepts may haveapplicability throughout the entire specification.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

What is claimed is:
 1. A method for discriminating a fault type in acontinuous in vivo analyte monitoring system, comprising: receiving asignal from an analyte monitor; receiving clinical context data;evaluating the clinical context data against clinical context criteriato determine clinical context information; discriminating the fault typebased on both the received signal from the analyte monitor and theclinical context information; and performing responsive processing basedon at least the discriminated fault type.
 2. The method of claim 1,wherein the discriminating includes categorizing the fault based on thereceived signal, the clinical context information, or both.
 3. Themethod of claim 2, wherein the categorizing the fault includescategorizing the fault as a sensor environment fault or as a systemerror/artifact fault.
 4. The method of claim 3, wherein thediscriminating includes categorizing the fault as a sensor environmentfault, and further comprising subcategorizing the fault as a compressionfault or an early wound response fault.
 5. The method of claim 1,wherein the discriminating includes slow versus fast sampling.
 6. Themethod of claim 1, wherein the received clinical context data isselected from the group consisting of age, anthropometric data, drugscurrently operating on the patient, temperature as compared to acriteria, a fault history of the patient, activity level of the patient,exercise level of the patient, a patient level of interaction with aglucose monitor, patterns of glucose signal values, clinical glucosevalue and its derivatives, a range of patient glucose levels over a timeperiod, a duration over which patient glucose levels are maintained in arange, a patient glucose state, a glycemic urgency index, time of day,and pressure.
 7. The method of claim 1, further comprising receiving anadditional signal.
 8. The method of claim 1, further comprisingreceiving an additional signal, wherein the additional signal is asensor temperature signal, an impedance signal, an oxygen signal, apressure signal, or a background signal.
 9. The method of claim 1,wherein the clinical context information corresponds to data about thepatient excluding a signal value measured at a sensor associated withthe analyte monitor.
 10. The method of claim 1, wherein the clinicalcontext criteria includes predefined values or ranges of parametersselected from the group consisting of drugs currently operating on thepatient, temperature, a fault history of the patient, activity level ofthe patient, exercise level of the patient, a patient level ofinteraction with a glucose monitor, patterns of glucose signal values,clinical glucose value and its derivatives, a range of patient glucoselevels over a time period, a duration over which patient glucose levelsare maintained in a range, a patient glucose state, a glycemic urgencyindex, time of day, and pressure.
 11. The method of claim 1, wherein theclinical context data includes temperature, the clinical contextcriteria includes a pattern of temperatures, the evaluating determinesthe clinical context information to be that the user is in contact withwater at the sensor site, and the discriminating the fault type includesdiscriminating the fault type as water ingress.
 12. The method of claim1, wherein the clinical context data includes patient activity level ortime of day, the clinical context criteria includes a pattern of patientactivity levels, the evaluating determines the clinical contextinformation to be that the user is compressing the sensor site, and thediscriminating the fault type includes discriminating the fault type ascompression.
 13. The method of claim 1, wherein the clinical contextdata includes time since implant, the clinical context criteria includesa range of times since implant in which dip and recover faults arelikely, the evaluating determines the clinical context information to bethat the sensor is recently implanted, and the discriminating the faulttype includes discriminating the fault type as a dip and recover fault.14. The method of claim 1, wherein the clinical context data includes aclinical glucose value and a datum selected from the group consisting ofage, anthropometric data, activity, exercise, clinical use of data, andpatient interaction with monitor.
 15. The method of claim 1, wherein theresponsive processing includes providing a display to a user, thedisplay including a warning, an alert, an alarm, a confidence indicator,a range of values, a predicted value, or a blank screen.
 16. The methodof claim 1, wherein the performing responsive processing includesadjusting a level of filtering of the received signal.
 17. The method ofclaim 1, wherein the performing responsive processing includesperforming a self diagnostics routine.
 18. The method of claim 1,wherein the performing responsive processing includes switching from afirst therapeutic mode to a second therapeutic mode.
 19. An electronicdevice for monitoring data associated with a physiological condition,comprising: a continuous glucose sensor, wherein the continuous glucosesensor is configured to substantially continuously measure theconcentration of glucose in the host, and to provide continuous sensordata associated with the glucose concentration in the host; and aprocessor module configured to perform the method of claim
 1. 20. Anelectronic device for delivering insulin to a host, the devicecomprising: a medicament delivery device configured to deliver insulinto the host, wherein the insulin delivery device is operably connectedto a continuous glucose sensor, wherein the continuous glucose sensor isconfigured to substantially continuously measure the concentration ofglucose in the host, and to provide continuous sensor data associatedwith the glucose concentration in the host; and a processor moduleconfigured to perform the method of claim 1.